Bifunctional heterocyclic compounds and methods of making and using same

ABSTRACT

The invention provides a family of compounds useful as anti-infective agents and/or anti-proliferative agents, for example, chemotherapeutic agents, anti-fungal agents, anti-bacterial agents, anti-parasitic agents, anti-viral agents, and/or anti-inflammatory agents, and/or prokinetic (gastrointestinal modulatory) agents, having the formula: 
                         
or pharmaceutically acceptable salts, esters, or prodrugs thereof.

RELATED APPLICATIONS

This application incorporates by reference and claims priority to U.S.Patent Application Nos. 60/414,207, filed Sep. 26, 2002, and 60/448,216,filed Feb. 19, 2003.

FIELD OF THE INVENTION

The present invention relates generally to the field of anti-infective,anti-proliferative, anti-inflammatory, and prokinetic agents, and moreparticularly, the invention relates to a family of bifunctionalheterocyclic compounds useful as such an agent.

BACKGROUND

The evolution of strains of cells or organisms resistant to currentlyeffective therapeutic agents is an ongoing medical problem. For example,the development of cancerous cells resistant to chemotherapeutic drugshas long been recognized as a problem in the oncology field. Onceresistant cells develop, the therapeutic regime, in order to remaineffective, must be modified to introduce other chemotherapeutic agents.Another example of this resistance problem is the development of strainsof microbial, fungal, parasitic and viral pathogens resistant to one ormore anti-infective agents. As a result, there is still a need for newanti-proliferative and anti-infective agents that are effective againststrains of cells or organisms that have developed resistance tocurrently available agents.

In the field of anti-infective agents, a variety of differentantibiotics have been developed and approved for use in humans over theyears. An oxazolidinone ring containing antibiotic known as linezolid(see, compound 1), available under the trade name Zyvox®, has beenapproved for use as an anti-bacterial agent active against Gram-positiveorganisms. Unfortunately, linezolid resistant strains of organisms arealready being reported (Tsiodras et al. (2001) LANCET 358: 207; Gonzaleset al. (2001) LANCET 357: 1179; Zurenko et al. (1999) PROCEEDINGS OF THE39^(TH) ANNUAL INTERSCIENCE CONFERENCE ON ANTIBACTERIAL AGENTS ANDCHEMOTHERAPY (ICAAC); San Francisco, Calif., USA, September 26–29).

Because linezolid is both a clinically effective and commerciallysignificant anti-microbial agent, investigators have been working todevelop other effective linezolid derivatives. Research has indicatedthat the oxazolidinone ring is important for linezolid activity. Theliterature commonly describes molecules having small groups substitutedat the C-5 of the oxazolidinone ring, and early structure-activityrelationships suggested that compounds with larger groups at the C-5position were less active as anti-bacterial agents. As a consequence, itis believed that, in general, investigators have been reluctant to placelarge substituents at the C-5 position of oxazolidinone rings inanti-microbial agents.

International patent publication no. WO 01/81350 discloses a series ofC-5 substituted oxazolidinones (s, general structure 2) where theacetamido group of linezolid was replaced, for example, with anoptionally substituted N-linked 5-membered heteroaryl ring or anN-linked 6-membered heteroaryl ring. The 5-membered heteroaryl ring maycontain either (i) one to three further nitrogen heteroatoms, or (ii) afurther heteroatom selected from O and S together with an optionalfurther nitrogen heteroatom; wherein the ring is optionally substitutedon a C-atom by an oxo or thioxo group; and/or is optionally substitutedon a C-atom by one or two C₁₋₄ alkyl groups; and/or on an availablenitrogen atom (provided that the ring is not thereby quaternized) byC₁₋₄ groups. The N-linked 6-membered heteroaryl ring may contain up tothree nitrogen heteroatoms in total, wherein the ring is substituted ona suitable C-atom by oxo or thioxo groups, and optionally substituted onany available C-atom by one or two C₁₋₄ alkyl groups.

In addition, International patent publication nos. WO 99/64416 and WO00/21960 also disclose a series of 5-substituted oxazolidinones (see,general structure 3). In particular, WO 99/64416 discloses compoundshaving the general structure 3, where X is —O— or —S— and HET is aC-linked 6-membered heteroaryl ring containing 1 or 2 nitrogen atoms. WO00/21960 discloses compounds having the general structure 3, where X is—N(H)— and HET is a C-linked 5-membered heteroaryl ring containing 2 to4 heteroatoms independently selected from N, O and S.

European Patent no. 0 097 469 B1 discloses intermediates of compound 4which are useful in the synthesis of triazole anti-fungal agents ofgeneral structure 5. The intermediates may contain a disubstituted C-5atom in the oxazolidinone ring, and the nitrogen atom of theoxazolidinone ring is a secondary amine.

Gregory and coworkers disclose the synthesis of a variety ofoxazolidinone containing antibacterial agents (Gregory et al. (1989) J.MED. CHEM. 32: 1673–1681). Compound 6, a C-5 substituted five-memberedheteroaryl derivative, was inactive as an antibacterial agent. Thisobservation appears to be consistent with other oxazolidinone containingcompounds that have the opposite stereochemical configuration at C-5relative to that found in linezolid.

Oxazolidinone compounds similar to those of compound 8 have been formedvia decomposition of substituted nitrosoureas 7 and have been useful asanticancer agents (Mulcahy et al. (1989) EUR J. CLIN. ONCOL. 5:1099–1104; Carmiati et al. (1989) BIOCHEM. PHARMACOL. 38: 2253–2258).

U.S. Pat. No. 6,034,069 discloses a series of 3′-N-modified6-O-substituted erythromycin ketolide derivatives similar to compound 9.The aryl group attached to the aminosaccharide moiety (represented by a3-pyridyl group in 9) was variable, and non-aryl substituents weresynthesized as well.

Published German patent application DE 196 04 223 A1 disclosesoxazolidinone ring-containing compounds of the general structure 10,where R₁ can be, in addition to other structures, a substituted orunsubstituted five-membered ring chosen from thienyl, furyl, pyrrolyl,pyrazolyl, thiazolyl, oxazolyl, imidazolyl and pyrrolidinyl.

U.S. Pat. No. 6,362,189 discloses antibiotic compounds having thegeneral formula 11. To the extent that the chemical moiety denoted bythe symbol “G” may be an oxazolidinone ring, the ring may be substitutedwith a thiocarbonyl functionality, namely a —CH₂NHC(S)R₁.

International patent publication no. WO 99/63937 proposes the synthesisof multivalent macrolide antibiotics comprising a portion of a macrolideantibiotic linked via a linker to a portion of another knownantibacterial agent. Two of the compounds proposed, although apparentlynot made or tested, include those shown below having the formulas 13aand 13b.

Notwithstanding the foregoing, there is still an ongoing need for newanti-infective and anti-proliferative agents. There is also an ongoingneed for new anti-inflammatory agents, and new agents to treatgastrointestinal motility disorders.

SUMMARY OF THE INVENTION

The invention provides a family of compounds useful as anti-infectiveagents and/or anti-proliferative agents, for example, chemotherapeuticagents, anti-fungal agents, anti-bacterial agents, anti-parasiticagents, anti-viral agents, and/or anti-inflammatory agents, and/orprokinetic (gastrointestinal modulatory) agents, having the formula:

or pharmaceutically acceptable salts, esters, or prodrugs thereof. Inthe formula, p and q independently are 0 or 1. Also, A, at eachoccurrence, independently is a carbon atom, a carbonyl group, or anitrogen atom. The B, D, E, and G groups can be selected from therespective groups of chemical moieties later defined in the detaileddescription.

In some embodiments, the invention provides a family of compounds havingthe formula:

or pharmaceutically acceptable salts, esters or prodrugs thereof. In theformula, p and q independently are 0 or 1. Also, A, at each occurrence,independently is a carbon atom or a nitrogen atom, provided that whenone A is a nitrogen atom, the other A is a carbon atom. The B, D, E, andG groups can be selected from the respective groups of chemical moietieslater defined in the detailed description.

In other embodiments, the invention provides a family of compoundshaving the formula:

or pharmaceutically acceptable salts, esters or prodrugs thereof. In theformula, p and q independently are 0 or 1. Also, A, at each occurrence,independently is a carbon atom or a nitrogen atom. The B D, E, and Ggroups can be selected from the respective groups of chemical moietieslater defined in the detailed description.

In another aspect, the invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of one or more of theforegoing compounds and a pharmaceutically acceptable carrier. In yetanother aspect, the invention provides a method for treating a microbialinfection, a fungal infection, a viral infection, a parasitic disease, aproliferative disease, an inflammatory disease, or a gastrointestinalmotility disorder in a mammal by administering effective amounts of thecompounds of the invention or pharmaceutical compositions of theinvention, for example, via oral, parenteral, or topical routes. Instill another aspect, the invention provides methods for synthesizingany one of the foregoing compounds. In another aspect, the inventionprovides a medical device, for example, a medical stent, which containsor is coated with one or more of the foregoing compounds.

The foregoing and other aspects and embodiments of the invention may bemore fully understood by reference to the following detailed descriptionand claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a family of compounds that can be used asanti-proliferative agents and/or anti-infective agents. The compoundsmay be used without limitation, for example, as anti-cancer agents,anti-bacterial agents, anti-fungal agents, anti-parasitic agents and/oranti-viral agents. Further, the present invention provides a family ofcompounds that can be used without limitation as anti-inflammatoryagents, for example, for use in treating chronic inflammatory airwaydiseases, and/or as prokinetic agents, for example, for use in treatinggastrointestinal motility disorders such as gastroesophageal refluxdisease, gastroparesis (diabetic and post surgical), irritable bowelsyndrome, and constipation.

1. Definitions

For the purpose of the present invention, the following definitions havebeen used throughout.

The carbon content of various hydrocarbon containing moieties isindicated by a prefix designating the minimum and maximum number ofcarbon atoms in the moiety, i.e., the prefix C_(i-j) defines the numberof carbon atoms present from the integer “i” to the integer “j”,inclusive. Thus, C₁₋₄ alkyl refers to alkyl of 1–4 carbon atoms,inclusive, or methyl, ethyl, propyl, and butyl, and isomeric formsthereof.

The terms “C₁₋₂ alkyl”, “C₁₋₃ alkyl”, “C₁₋₄ alkyl”, “C₁₋₅ alkyl”, “C₁₋₆alkyl”, “C₁₋₈ alkyl”, “C₁₋₁₀ alkyl”, and “C₁₋₁₆ alkyl” refer to an alkylgroup having one to two, one to three, one to four, one to five, one tosix, one to eight, one to ten, or one to sixteen carbon atoms,respectively such as, for example, methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl,tetradecyl and their isomeric forms thereof.

The terms “C₂₋₅ alkenyl”, “C₂₋₆ alkenyl”, “C₂₋₈ alkenyl”, and “C₂₋₁₆alkenyl” refer to at least one double bond alkenyl group having two tofive, two to six, two to eight, or two to sixteen carbon atoms,respectively such as, for example, ethenyl, propenyl, butenyl, pentenyl,pentdienyl, hexenyl, hexadienyl, heptenyl, heptdienyl, octenyl,octdienyl, octatrienyl, nonenyl, nonedienyl, nonatrienyl, undecenyl,undecdienyl, dodecenyl, tridecenyl, tetradecenyl and their isomericforms thereof.

The terms “C₂₋₅ alkynyl”, “C₂₋₆ alkynyl”, and “C₂₋₈ alkynyl” refer to atleast one triple bond alkynyl group having two to five, two to six, ortwo to eight carbon atoms, respectively such as, for example, ethynyl,propynyl, butynyl, pentynyl, pentdiynyl, hexynyl, hexdiynyl, heptynyl,heptdiynyl, octynyl, octdiynyl, octatriynyl, and their isomeric formsthereof.

The terms “C₃₋₄ cycloalkyl”, “C₃₋₆ cycloalkyl”, “C₅₋₆ cycloalkyl”, “C₃₋₇cycloalkyl”, and “C₃₋₈ cycloalkyl” refer to a cycloalkyl group havingthree to four, three to six, five to six, three to seven, or three toeight carbon atoms, respectively such as, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and theirisomeric forms thereof.

The terms “C₁₋₄ alkoxy”, “C₁₋₅ alkoxy”, “C₁₋₆ alkoxy”, and “C₁₋₈alkoxy”, refer to an alkyl group having one to four, one to five, one tosix, or one to eight carbon atoms, respectively attached to an oxygenatom such as, for example, methoxy, ethoxy, propyloxy, butyloxy,pentyloxy, hexyloxy, heptyloxy, or octyloxy and their isomeric formsthereof.

The term “C₁₋₆ hydroxy” refers to an alkyl group having one to sixcarbon atoms, and isomeric forms thereof, attached to a hydroxy group.

The terms “C₁₋₃ acyl”, “C₁₋₄ acyl”, “C₁₋₅ acyl”, “C₁₋₆ acyl”, and “C₁₋₈acyl” refer to a carbonyl group having an alkyl group of one to three,one to four, one to five, one to six, or one to eight carbon atoms,respectively.

The terms “C₁₋₄ alkoxycarbonyl”, and “C₁₋₆ alkoxycarbonyl” refer to anester group having an alkyl group of one to four, or one to six carbonatoms, respectively.

The terms “C₁₋₆ alkylthio” and “C₁₋₈ alkylthio” refer to an alkyl grouphaving one to six or one to eight carbon atoms respectively and isomericforms thereof attached to a sulfur atom.

The term “C₁₋₃ alkylamino” refers to alkyl groups having from one tothree carbon atoms attached to an amino moiety such as, for example,dimethylamino, methylethylamino, diethylamino, dipropylamino,methylpropylamino, or ethylpropylamino and their isomeric forms thereof.

The term “Het” refers to 5 to 10 membered saturated, unsaturated oraromatic heterocyclic rings containing one or more oxygen, nitrogen, andsulfur forming such groups as, for example, pyridine, thiophene, furan,pyrazoline, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl,2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl,4-oxo-2-imidazolyl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl,2-oxazolyl, 4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl,4,5,-dihydrooxazole, 1,2,3-oxathiole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole,2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl,2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, benzoisothiazole,benzisoxazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl,3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl,1,2,3,-oxathiazole-1-oxide, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl,1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl, 1,2,4-triazol-3-yl,1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl,1-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-tetrazolyl,1-indolyl, 1-indazolyl, 2-isoindolyl, 7-oxo-2-isoindolyl, 1-purinyl,3-isothiazoly, 4-isothiazolyl and 5-isothiazolyl, 1,3,4,-oxadiazole,4-oxo-2-thiazolinyl, or 5-methyl-1,3,4-thiadiazol-2-yl, thiazoledione,1,2,3,4-thiatriazole, 1,2,4-dithiazolone. Each of these moieties may besubstituted as appropriate.

The terms “halo” or “halogen” refers to a fluorine atom, a chlorineatom, a bromine atom, and/or an iodine atom.

The term “hydroxy protecting group” refers to an easily removable groupwhich is known in the art to protect a hydroxyl group againstundesirable reaction during synthetic procedures and to be selectivelyremovable. The use of hydroxy-protecting groups is well known in the artfor protecting groups against undesirable reactions during a syntheticprocedure and many such protecting groups are known (see, for example,T. H. Greene and P. G. M. Wuts (1999) PROTECTIVE GROUPS IN ORGANICSYNTHESIS, 3rd edition, John Wiley & Sons, New York). Examples ofhydroxy protecting groups include, but are not limited to, acetate,methoxymethyl ether, methylthiomethyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, acyl substituted with an aromatic group and thelike.

The term “aryl” refers to a mono- or bicyclic carbocyclic ring systemhaving one or two aromatic rings including, but not limited to, phenyl,naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like.

The term “substituted aryl” refers to an aryl group, as defined herein,substituted by independent replacement of one, two, three, four, or fiveof the hydrogen atoms thereon with substituents independently selectedfrom alkyl, substituted alkyl, haloalkyl, alkoxy, thioalkoxy, amino,alkylamino, dialkylamino, acylamino, cyano, hydroxy, halo, mercapto,nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. Morespecifically, the substituents may be F, Cl, Br, I, OH, NO₂, CN,C(O)—C₁₋₆ alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl, CO₂-aryl,CO₂-heteroaryl, CONH₂, CONH—C₁₋₆ alkyl, CONH-aryl, CONH-heteroaryl,OC(O)—C₁₋₆ alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO₂-alkyl, OCO₂-aryl,OCO₂-heteroaryl, OCONH₂, OCONH—C₁₋₆ alkyl, OCONH-aryl, OCONH-heteroaryl,NHC(O)—C₁₋₆ alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO₂-alkyl,NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂, NHCONH—C₁₋₆ alkyl, NHCONH-aryl,NHCONH-heteroaryl, SO₂—C₁₋₆ alkyl, SO₂-aryl, SO₂-heteroaryl, SO₂NH₂,SO₂NH—C₁₋₆ alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, C₁₋₆ alkyl, C₃₋₆cycloalkyl, CF₃, CH₂CF₃, CHCl₂, CH₂OH, CH₂CH₂OH, CH₂NH₂, CH₂SO₂CH₃,aryl, heteroaryl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C₁₋₆alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino,heteroarylamino, C₁₋₃ alkylamino, thio, aryl-thio, heteroarylthio,benzyl-thio, C₁₋₆ alkyl-thio, or methylthiomethyl. In addition,substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term “arylalkyl group” refers to an aryl group attached to an alkylgroup. An example of an arylalkyl group is a benzyl group.

The term “substituted arylalkyl group” refers to an aryl group orsubstituted aryl group attached to an alkyl group or a substituted alkylgroup, provided that one or both of the aryl and alkyl groups aresubstituted.

The term “heteroaryl” refers to a cyclic aromatic radical having fromfive to ten ring atoms of which one ring atom is selected from S, O andN; zero, one, two, or three ring atoms are additional heteroatomsindependently selected from S, O and N; and the remaining ring atoms arecarbon, the radical being joined to the rest of the molecule via any ofthe ring atoms, such as, for example, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.

The term “substituted heteroaryl” refers to a heteroaryl group asdefined herein, substituted by independent replacement of one, two,three, four, or five of the hydrogen atoms thereon with F, Cl, Br, I,OH, NO₂, CN, C(O)—C₁₋₆ alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl,CO₂-aryl, CO₂-heteroaryl, CONH₂, CONH—C₁₋₆ alkyl, CONH-aryl,CONH-heteroaryl, OC(O)—C₁₋₆ alkyl, OC(O)-aryl, OC(O)-heteroaryl,OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl, OCONH₂, OCONH—C₁₋₆ alkyl,OCONH-aryl, OCONH-heteroaryl, NHC(O)—C₁₋₆ alkyl, NHC(O)-aryl,NHC(O)-heteroaryl, NHCO₂-alkyl, NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂,NHCONH—C₁₋₆ alkyl, NHCONH-aryl, NHCONH-heteroaryl, SO₂—C₁₋₆ alkyl,SO₂-aryl, SO₂-heteroaryl, SO₂NH₂, SO₂NH—C₁₋₆ alkyl, SO₂NH-aryl,SO₂NH-heteroaryl, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, CF₃, CH₂CF₃, CHCl₂,CH₂OH, CH₂CH₂OH, CH₂NH₂, CH₂SO₂CH₃, aryl, heteroaryl, benzyl, benzyloxy,aryloxy, heteroaryloxy, C₁₋₆ alkoxy, methoxymethoxy, methoxyethoxy,amino, benzylamino, arylamino, heteroarylamino, C₁₋₃ alkylamino, thio,aryl-thio, heteroarylthio, benzyl-thio, C₁₋₆ alkyl-thio, ormethylthiomethyl.

The term “heterocyclic” refers to heterocycloalkyl and heteroaryl. Theterm “substituted heterocyclic,” as used herein, refers to substitutedheterocycloalkyl and substituted heteroaryl.

The term “macrolide” refers to any compound possessing a 14- or15-macrocyclic ring, and derivatives thereof (such as keto, oxime,cyclic carbonate derivatives). These include, for example, compoundsthat are (or are synthetically derived from) known antibacterial agentsincluding, but not limited to, erythromycin, clarithromycin,azithromycin, telithromycin, roxithromycin, pikromycin, flurithromycin,and dirithromycin.

In the formulas herein, a broken or dashed circle within a ringindicates that the ring is either aromatic or non-aromatic. A bondextending from a chemical moiety that is depicted as crossing a bond ina ring, but is not attached directly to a ring atom, indicates that thechemical moiety may be bonded to any atom of the ring. As to any of theabove chemical moieties that contain one ore more substituents, it isunderstood that such moieties do not contain any substitution orsubstitution patterns that are sterically impractical and/orsynthetically unfeasible. In addition, the compounds of this inventioninclude all stereochemical isomers arising from the substitution ofthese moieties.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describe pharmaceutically acceptable salts in detail in J. PHARMSCIENCES 66: 1–19 (1977). The salts can be prepared in situ during thefinal isolation and purification of the compounds of the invention, orseparately by reacting the free base function with a suitable organicacid. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids (such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid), or with organic acids (such as acetic acid, oxalicacid, maleic acid, tartaric acid, citric acid, succinic acid or malonicacid), or by using other methods used in the art (such as ion exchange).Other pharmaceutically acceptable salts include adipate, alginate,ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

The term “pharmaceutically acceptable ester” refers to esters thathydrolyze in vivo and include those that break down readily in the humanbody to leave the parent compound or a salt thereof. Suitable estergroups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Other suitableester groups include, for example, those derived from pharmaceuticallyacceptable alcohols, such as stright-chain or branched aliphaticalcohols, benzylic alcohols, and amino-alcohols. Examples of particularesters include formates, acetates, propionates, butyrates, acrylates,ethylsuccinates, and methyl, ethyl, propyl, benzyl, and 2-aminoethylalcohol esters.

The term “pharmaceutically acceptable prodrugs” refers to those prodrugsof the compounds of the present invention which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals with undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms, where possible, of the compounds of the invention. The term“prodrug” refers to compounds that are rapidly transformed in vivo toyield the parent compound of the previously formula, for example byhydrolysis in blood. A thorough discussion is provided in T. Higuchi andV. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S.Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press,1987.

The term “physiologically acceptable cation” refers to common,positively charged species such as (but not limited to) metals such assodium, potassium, calcium, magnesium, zinc and the like. The cation canalso be an organic species such as an amine salt. Non-limiting examplesof such amine salts can be the protonated form of methylamine,ethylamine, cyclohexylamine, lysine, N-methylglucamine, diethanolamine,triethanolamine, tris-(hydroxymethyl)aminomethane, piperidine,morpholine, and the like.

The term “electron-withdrawing group” refers to groups well known tothose in the art capable of pulling electron density towards the groupand away from a source (such as an aromatic ring, an olefin, acarbonyl-like group or a sigma bond between two designated atoms).Examples of such electron-withdrawing groups are, for example, nitro,keto, formyl, acyl, halogens, carboxy, trihaloalkyl, sulfonyl and thelike.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes aredescribed as having, including, or comprising specific process steps, itis contemplated that compositions of the present invention also consistessentially of, or consist of, the recited components, and that theprocesses of the present invention also consist essentially of, orconsist of, the recited processing steps. Further, it should beunderstood that the order of steps or order for performing certainactions are immaterial so long as the invention remains operable.Moreover, two or more steps or actions may be conducted simultaneously.

2. Compounds of the Invention

In one aspect, the invention provides compounds having the formula:

or a pharmaceutically acceptable salt, ester, or prodrug thereof,

wherein

A, at each occurrence, independently is carbon, carbonyl, or nitrogen,provided at least one A is carbon;

Z is carbon, nitrogen, oxygen, or sulfur;

B is selected from the group consisting of O, NR², S(O)_(r), C═O, C═S,and C═NOR³,

p is 0 or 1;

q, at each occurrence, independently is 0 or 1;

r is 0, 1, or 2;

R², at each occurrence, independently is selected from the groupconsisting of:

-   -   a) hydrogen, b) S(O)_(r)R⁴, c) formyl, d) C₁₋₈ alkyl, e) C₂₋₈        alkenyl, f) C₂₋₈ alkynyl, g) C₁₋₈ alkoxy, h) C₁₋₈ alkylthio, i)        C₁₋₈ acyl, j) saturated, unsaturated, or aromatic C₃₋₈        carbocycle, and k) saturated, unsaturated, or aromatic 5–10        membered heterocycle containing one or more heteroatoms selected        from the group consisting of nitrogen, oxygen, and sulfur,        -   wherein any of d)–k) optionally is substituted with one or            more moieties selected from the group consisting of            carbonyl, aryl, substituted aryl, heteroaryl, substituted            heteroaryl, F, Cl, Br, I, CN, NO₂, —NR³R³, —OR³,            —S(O)_(r)R⁴, —S(O)_(r)NR³R³, —C(O)R³, —C(O)OR³, —OC(O)R³,            —C(O)NR³R³, and —OC(O)NR³R³;

alternatively, two R² groups, taken together with the atom to which theyare bonded, form i) 5–8 membered saturated or unsaturated carbocycle, orii) 5–8 membered saturated or unsaturated heterocycle containing one ormore atoms selected from the group consisting of nitrogen, oxygen, andsulfur,

-   -   wherein i)–ii) optionally is substituted with one or more        moieties selected from the group consisting of carbonyl, F, Cl,        Br, I, CN, NO₂, —NR³R³, —OR³, —S(O)_(r)R⁴, —S(O)_(r)NR³R³,        —C(O)R³, —C(O)OR³, —OC(O)R³, —C(O)NR³R³, —OC(O)NR³R³, C₁₋₆ acyl,        aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R³, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) hydrogen, b) C₁₋₈ alkyl, c) C₂₋₈ alkenyl, d) C₂₋₈ alkynyl, e)        C₁₋₈ acyl, f) saturated, unsaturated, or aromatic C₃₋₈        carbocycle, and g) saturated, unsaturated, or aromatic 5–10        membered heterocycle containing one or more heteroatoms selected        from the group consisting of nitrogen, oxygen, and sulfur,        -   wherein any of b)–h) optionally is substituted with one or            more moieties selected from the group consisting of            carbonyl, F, Cl, Br, 1, CN, NO₂, —NR⁶R⁶, —OR⁶, —S(O)_(r)R⁶,            —S(O)_(r)NR⁶R⁶, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —C(O)NR⁶R⁶,            —OC(O)NR⁶R⁶, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl,            and substituted heteroaryl;

alternatively, two R³ groups, taken together with the atom to which theyare bonded, form i) a 5–7 membered saturated or unsaturated carbocycle,or ii) a 5–7 membered saturated or unsaturated heterocyocle containingone or more atoms selected from the group consisting of nitrogen,oxygen, and sulfur,

-   -   wherein i)–ii) optionally is substituted with one or more        moieties selected from the group consisting of carbonyl, F, Cl,        Br, I, CN, NO₂, —NR⁶R⁶, —OR⁶, —S(O)_(r)R⁶, —S(O)_(r)NR⁶R⁶,        —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶, —C(O)NR⁶R⁶, —OC(O)NR⁶R⁶, C₁₋₆ acyl,        aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R⁴ is selected from the group consisting of:

-   -   a) hydrogen, b) —NR³R³, c) —NR³OR³, d) —NR³NR³R³ e)        —NHC(O)R³, f) —C(O)NR³R³, g) —N₃, h) C₁₋₈ alkyl, i) C₂₋₈        alkenyl, j) C₂₋₈ alkynyl, k) saturated, unsaturated, or aromatic        C₃₋₈ carbocycle, and l) saturated, unsaturated, or aromatic 5–10        membered heterocycle containing one or more heteroatoms selected        from the group consisting of nitrogen, oxygen, and sulfur,        -   wherein any of h)–l) optionally is substituted with one or            more moieties selected from the group consisting of            carbonyl, F, Cl, Br, I, CN, NO₂, —NR³R³, —OR³, —SR³,            —S(O)_(r)R⁵, —S(O)_(r)NR³R³, —C(O)R³, —C(O)OR³, —OC(O)R³,            —C(O)NR³R³, —OC(O)NR³R³, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆            alkynyl, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl, and            substituted heteroaryl;

R⁵ is selected from the group consisting of:

-   -   a) hydrogen, b) —NR³R³, c) —NR³OR³, d) —NR³NR³R³ e)        —NHC(O)R³, f) —C(O)NR³R³, g) —N₃, h) C₁₋₈ alkyl, i) C₂₋₈        alkenyl, j) C₂₋₈ alkynyl, k) saturated, unsaturated, or aromatic        C₃₋₈ carbocycle, and 1) saturated, unsaturated, or aromatic 5–10        membered heterocycle containing one or more heteroatoms selected        from the group consisting of nitrogen, oxygen, and sulfur,        -   wherein any of h)–l) optionally is substituted with one or            more moieties selected from the group consisting of F, Cl,            Br, I, CN, NO₂, —NR³R³, —OR³, —SR³—C(O)R³, —C(O)OR³,            —OC(O)R³, —C(O)NR³R³, —OC(O)NR³R³, C₁₋₆ alkyl, C₁₋₆ alkenyl,            C₁₋₆ alkynyl, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl,            and substituted heteroaryl; and

R⁶, at each occurrence, independently is selected from the groupconsisting of:

-   -   hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, C₁₋₆ acyl,        aryl, substituted aryl, hetreroaryl, substituted heteroaryl;

alternatively, two R⁶ groups taken together are —(CH₂)_(s)—,

-   -   wherein s is 1, 2, 3, 4, or 5;

D-E is selected from the group consisting of:

E is selected from the group consisting of:

d) 5–10 membered saturated, unsaturated, or aromatic heterocyclecontaining one or more heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur, and optionally substituted with one ormore R¹³ groups;

e) C₅₋₁₀ saturated, unsaturated, or aromatic carbocycle, optionallysubstituted with one or more R¹³ groups;

f) C₁₋₈alkyl,

g) C₂₋₈ alkenyl,

h) C₃₋₈ alkynyl,

i) C₁₋₈alkoxy,

j) C₁₋₈ aklylthio,

k) C₁₋₈ acyl,

l) S(O)_(r)R⁵; and

m) hydrogen,

n) a β-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring,wherein the β-carbolin-3-yl, or indolizinyl optionally is substitutedwith one to three R³⁰ groups;

wherein any of f)–k) optionally is substituted with

-   -   i) one or more R¹³ groups;    -   ii) 5–6 membered saturated, unsaturated, or aromatic heterocycle        containing one or more heteroatoms selected from the group        consisting of nitrogen, oxygen, and sulfur, and optionally        substituted with one or more R¹³ groups; or    -   iii) C₅₋₁₀ saturated, unsaturated, or aromatic carbocycle,        optionally substituted with one or more R¹³ groups;

R⁷ is selected from the group consisting of:

-   -   a) hydrogen, b) carbonyl, c) formyl, d) F, e) Cl, f) Br, g)        I, h) CN, i) NO₂, j) OR³, k) —S(O)_(r)R⁵, l) —S(O)_(i)N═R², m)        —C(O)R², n) —C(O)OR³, o) —OC(O)R², p) —C(O)NR²R², q)        —OC(O)NR²R², r) —C(═NR¹²)R², s) —C(R²)(R²)OR³, t)        —C(R²)(R²)OC(O)R², u) —C(R²)(OR³)(CH₂)_(r)NR²R², v) —NR²R², w)        —NR²OR³, x) —N(R²)C(O)R², y) —N(R²)C(O)OR³, z) —N(R²)C(O)NR²R²,        aa) —N(R²)S(O)_(r)R⁵, bb) —C(OR⁶)(OR⁶)R², cc) —C(R²)(R³)NR²R²,        dd) —C(R²)(R³)NR²R¹², ee)═NR¹², ff) —C(S)NR²R², gg)        —N(R²)C(S)R², hh) —OC(S)NR²R², ii) —N(R²)C(S)OR³, jj)        —N(R²)C(S)NR²R², kk) —SC(O)R², ll) C₁₋₈ alkyl, mm) C₂₋₈ alkenyl,        nn) C₂₋₈ alkynyl, oo) C₁₋₈ alkoxy, pp) C₁₋₈ alkylthio, qq) C₁₋₈        acyl, rr) saturated, unsaturated, or aromatic C₅₋₁₀ carbocycle,        and ss) saturated, unsaturated, or aromatic 5–10 membered        heterocycle containing one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur,        -   wherein any of ll)–ss) optionally is substituted with one or            more moieties selected from the group consisting of:        -   carbonyl; formyl; F; Cl; Br; I; CN; NO₂; OR³; —S(O)_(r)R⁵;            —S(O)_(r)N═R², —C(O)R²; —C(O)OR³; —OC(O)R²; —C(O)NR²R²;            —OC(O)NR²R²; —C(═NR¹⁰)R²; —C(R²)(R²)OR³; —C(R²)(R²)OC(O)R²;            —C(R²)(OR³)(CH₂)_(r)NR²R²; —NR²R²; —NR²OR³; —NR²C(O)R²;            —NR²C(O)OR³; —NR²C(O)NR²R²; —NR²S(O)_(r)R⁵; —C(OR⁶)(OR⁶)R²;            —C(R²)(R³)NR²R²; —C(R²)(R³)NR²R¹²; ═NR¹²; —C(S)NR²R²;            —NR²C(S)R²; —OC(S)NR²R²; —NR²C(S)OR³; —NR²C(S)NR²R²;            —SC(O)R²; C₂₋₅ alkenyl; C₂₋₅ alkynyl; C₁₋₈ alkoxy; C₁₋₈            alkylthio; C₁₋₈ acyl; saturated, unsaturated, or aromatic            C₅₋₁₀ carbocycle, optionally substituted with one or more R⁸            groups; and saturated, unsaturated, or aromatic 5–10            membered heterocycle containing one or more heteroatoms            selected from the group consisting of nitrogen, oxygen, and            sulfur, and optionally substituted with one or more R⁸            groups;

R⁸ is selected from the group consisting of:

-   -   hydrogen; F; Cl; Br; I; CN; NO₂; OR⁶; aryl; substituted aryl;        heteroaryl; substituted heteroaryl; and C₁₋₆ alkyl, optionally        substituted with one or more moieties selected from the group        consisting of aryl, substituted aryl, heteroaryl, substituted        heteroaryl, F, Cl, Br, I, CN, NO₂, and OR⁶;

alternatively, R⁷ and R⁸ taken together are —O(CH₂)_(r)O—;

R⁹, at each occurrence, independently is selected from the groupconsisting of:

-   -   hydrogen, F, Cl, Br, I, CN, OR³, NO₂, —NR²R², C₁₋₆ alkyl, C₁₋₆        acyl, and C₁₋₆ alkoxy;

R¹⁰ is selected from the group consisting of:

-   -   a) saturated, unsaturated, or aromatic C₅₋₁₀ carbocycle,    -   b) saturated, unsaturated, or aromatic 5–10 membered heterocycle        containing one or more heteroatoms selected from the group        consisting of nitrogen, oxygen, and sulfur,    -   c) —X—C₁₋₆ alkyl-saturated, unsaturated, or aromatic 5–10        membered heterocycle containing one or more heteroatoms selected        from the group consisting of nitrogen, oxygen, and sulfur,        -   wherein X is O or NR³,    -   d) saturated, unsaturated, or aromatic 10-membered bicyclic ring        system optionally containing one or more heteroatoms selected        from the group consisting of nitrogen, oxygen, and sulfur,    -   e) saturated, unsaturated, or aromatic 13-membered tricyclic        ring system optionally containing one or more heteroatoms        selected from the group consisting of nitrogen, oxygen, and        sulfur,

-   -   w) a diazinyl group,    -   x) a triazinyl group,    -   y) a quinolinyl group,    -   z) a quinoxalinyl group,    -   aa) a naphthyridinyl group,    -   bb)

-   -   ll) —C(O)CH₃, and    -   mm) R⁹,    -   wherein any of a)–kk) optionally is substituted with one or more        R¹³ groups;

alternatively, R¹⁰ and one R⁹ group taken together is

or

alternatively, R¹⁰ and one R⁹ group, taken together with the atoms towhich they are bonded, form a 5–7 membered saturated or unsaturatedcarbocycle, optionally substituted with one or more R¹³ groups; or a 5–7membered saturated or unsaturated heterocyocle containing one or moreatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and optionally substituted with one or more R¹³ groups;

R¹¹ at each occurrence, independently is selected from the groupconsisting of:

-   -   hydrogen; an electron-withdrawing group; aryl; substituted aryl;        heteroaryl; substituted heteroaryl; and C₁₋₆ alkyl, optionally        substituted with F, Cl, or Br;

alternatively, any R¹¹ and R⁸, taken together with the atoms to whichthey are bonded, form a 5–7 membered saturated or unsaturatedcarbocycle, optionally substituted with one or more R¹³ groups; or a 5–7membered saturated or unsaturated heterocycle containing one or moreatoms selected from the group consisting of nitrogen, oxygen, andsulfur, and optionally substituted with one or more R¹³ groups;

alternatively, any R¹¹ and R⁸, taken together with the atoms to whichthey are bonded, form —(CH₂)_(k)— or a 5-, 6-, or 7-membered ring havingthe formula:

-   -   wherein        -   u is 2, 3, 4, or 5;

R¹² is selected from the group consisting of:

-   -   —NR²R², —OR³, —OC(O)R², —OC(O)OR³, —NR²C(O)R², —NR²C(O)NR²R²,        —NR²C(S)NR²R², and —NR²C(═NR²)NR²R²;

R¹³, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) hydrogen, b) carbonyl, c) formyl d) F, e) Cl, f) Br, g) I, h)        CN, i) NO₂, j) OR³, k) —S(O)_(r)R⁵, l) —S(O)_(r)N═R³, m)        —C(O)R², n) —C(O)OR³, o) —OC(O)R², p) —C(O)NR²R², q)        —OC(O)NR²R², r) —C(═NR²)R², s) —C(R²)(R²)OR³, t)        —C(R²)(R²)OC(O)R², u) —C(R²)(OR³)(CH₂)_(r)NR²R², v) —NR²R², w)        —NR²OR³, x) —N(R²)C(O)R², y) —N(R²)C(O)OR³, z) —N(R²)C(O)NR²R²,        aa) —N(R²)S(O)_(r)R⁵, bb) —C(OR⁶)(OR⁶)R², cc) —C(R²)(R³)NR²R²,        dd) —C(R²)(R³)NR²R¹², ee) ═NR¹², ff) —C(S)NR²R², gg)        —N(R²)C(S)R², hh) —OC(S)NR²R², ii) —N(R²)C(S)OR³, jj)        —N(R²)C(S)NR²R², kk) —SC(O)R², ll) C₁₋₈ alkyl, mm) C₂₋₈ alkenyl,        nn) C₂₋₈ alkynyl, oo) C₁₋₈ alkoxy, pp) C₁₋₈ alkylthio, qq) C₁₋₈        acyl, rr) saturated, unsaturated, or aromatic C₅₋₁₀ carbocycle,        ss) saturated, unsaturated, or aromatic 5–10 membered        heterocycle containing one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur, tt) saturated,        unsaturated, or aromatic 10-membered bicyclic ring system        optionally containing one or more heteroatoms selected from the        group consisting of nitrogen, oxygen, and sulfur, and uu)        saturated, unsaturated, or aromatic 13-membered tricyclic ring        system optionally containing one or more heteroatoms selected        from the group consisting of nitrogen, oxygen, and sulfur,        -   wherein any of ll)–uu) optionally is substituted with one or            more moieties selected from the group consisting of:        -   carbonyl; formyl; F; Cl; Br; I; CN; NO₂; OR³; —S(O)_(r)R⁵;            —S(O)_(r)N═R², —C(O)R²; —C(O)OR³; —OC(O)R²; —C(O)NR²R²;            —OC(O)NR²R²; —C(═NR¹²)R²; —C(R²)(R²)OR³; —C(R²)(R²)OC(O)R²;            —C(R²)(OR³)(CH₂)_(r)NR²R²; —NR²R²; —NR²OR³; —NR²C(O)R²;            —NR²C(O)OR³; —NR²C(O)NR²R²; —NR²S(O)_(r)R⁵; —C(OR⁶)(OR⁶)R²;            —C(R²)(R³)NR²R²; —C(R²)(R³)NR²R¹²; ═NR¹²; —C(S)NR²R²;            —NR²C(S)R²; —OC(S)NR²R²; —NR²C(S)OR³; —NR²C(S)NR²R²;            —SC(O)R²; C₁₋₈ alkyl, C₂₋₈ alkenyl; C₂₋₈ alkynyl; C₁₋₈            alkoxy; C₁₋₈ alkylthio; C₁₋₈ acyl; saturated, unsaturated,            or aromatic C₃₋₁₀ carbocycle optionally substituted with one            or more R⁷ groups; and saturated, unsaturated, or aromatic            3–10 membered heterocycle containing one or more heteroatoms            selected from the group consisting of nitrogen, oxygen, and            sulfur, and substituted with one or more R⁷ groups;

A′ is CH, N, S, or O;

B′ is O, S, or NR²;

D′ is an unsaturated 4-atom linker containing one nitrogen atom andthree carbon atoms, which forms a pyridyl ring fused with the heteroarylmoiety;

E′ is O, NR⁵¹, or S(O)_(r);

G′ is —CH₂—, —CH₂CH₂—, —CH₂(OH)CH₂—, —C(O)—, or —CH₂CH₂CH₂—;

J′ is —S(O)_(r)—, —O—, or —NR³⁶—;

K′ is CH₂, O, S, or NR²;

R³⁰ is selected from the group consisting of:

-   -   a) carbonyl, b) formyl, c) F, d) Cl, e) Br, f) CN, g) —OR³, h)        —SR³, i) —CF₃, j) —NO₂, k) —NR²R², l) —NR³⁸R³⁸, m)

-   -   n) C₁₋₆ alkyl, o) C₂₋₆ alkenyl, p) C₂₋₆ alkynyl, q) C₁₋₆        alkoxy, r) —C(O)—C₁₋₆ alkyl, s) C₁₋₆ alkylthio, t) C₁₋₆ acyl, u)        C₂₋₈ alkenylphenyl, v) aryl, and w) heteroaryl,        -   wherein any of n)–w) optionally is substituted with one or            more R³⁹ groups;

R³¹, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) hydrogen, b) carbonyl, c) F, d) Cl, e) Br, f) —CN, g)        formyl, h) —NO₂, i) —OR³, j) —NR²R², k) aryl, l) substituted        aryl, m) heteroaryl, n) substituted aryl, o) C₁₋₆ alkyl, p) C₂₋₆        alkenyl, q) C₂₋₆ alkynyl, r) C₁₋₆ alkylthio, s) C₁₋₆ acyl, t)        C₁₋₆ alkoxy, and u) —C(O)C₁₋₆ alkoxy,    -   wherein any of o)–u) optionally is substituted with one or more        moieties from the group consisting of:        -   —N(phenyl)(CH₂CH₂OH), —OCH(CH₃)(OCH₂CH₃),            —O-phenyl-[para-NHC(O)CH₃], and R¹³;

R³², at each occurrence, independently is selected from the groupconsisting of:

-   -   a) hydrogen, b) carbonyl, c) formyl, d) —OR⁴³, e) —NR⁴⁴R⁴⁴, f)        —S(O)_(r)R⁴⁷, g) —S(O)_(r)NR⁴⁴R⁴⁴, h) aryl, i) substituted        aryl, j) heteroaryl, k) substituted heteroaryl, l) C₁₋₆        alkyl, m) C₂₋₆ alkenyl, n) C₂₋₆ alkynyl o) C₁₋₆ alkylthio, p)        C₁₋₆ acyl, q) C₁₋₆ alkoxy, r) —C(O)—C₁₋₆ alkoxy,

-   -   wherein any of n)–w) optionally is substituted with one or more        moieties from the group consisting of:        -   —N(phenyl)(CH₂CH₂OH), —OCH(CH₃)(OCH₂CH₃),            —O-phenyl-[para-NHC(O)CH₃] and R¹³;

R³³ is hydrogen, F, Cl, Br, C₁₋₆ alkyl, or C₁₋₆ alkyl-aryl;

R³⁴ is hydrogen or CH₃;

R³⁵ is selected from the group consisting of:

-   -   hydrogen, —OH, —CH₃, —OCH₃, —NHC(O)OR², —NHC(O)CH₂OR³,        —C(O)O—C₁₋₆ alkyl, —CH₂OH, —NHOCH₃, —C(O)O—C₁₋₆alkyl, —C(O)CH₃,        —CH₂C(O)CH₃,

alternatively, R³⁴ and R³⁵ taken together are a carbonyl, ═NR⁴⁸, or

R³⁶ is selected from the group consisting of:

-   -   —C(O)OR³, —C(O)C(R⁵⁰)(R⁵⁰)(OR³), —C(O)R², —SO₂R⁴,        —C(O)(CH₂)₂C(O)CH₃, —C(O)CH₂OH, —(CH₂)₂R², —C(O)CH₂OC(O)R²,        —CH₂CN, —CH₂CHF₂, —SO₂NR²R², —NHC(O)CH₂N(CH₃)₂,

R³⁷ is selected from the group consisting of:

-   -   —C(O)CH₃, —C(O)H, —C(O)CHCl₂, —C(O)CH₂OH, —SO₂CH₃,        —C(O)CH₂OC(O)CH₃, —C(O)CHF₂, —C(O)CH₂OC(O)H, —C(O)CH₂OCH₂—C≡CH,        —C(O)CH₂OCH₂C₆H₅,

R³⁸, at each occurrence, independently is selected from the groupconsisting of:

-   -   hydrogen, formyl, C₁₋₄ alkyl, C₁₋₄ acyl, aryl, C₃₋₆ cycloalkyl,        —P(O)(OR³)(OR³), and —SO₂R⁴;

alternatively, two R³⁸ groups taken together with the atom to which theyare bonded form a 5- or 6-membered saturated heterocyclic groupcontaining one or more atoms selected from the group consisting ofnitrogen, oxygen, and sulfur, and optionally substituted with phenyl,pyrimidyl, C₁₋₃ alkyl, or C₁₋₃ acyl;

R³⁹ is selected from the group consisting of:

-   -   a) carbonyl, b) formyl, c) F, d) Cl, e) Br, f) I, g) CN, h)        —OR³, i) —SR³, j) —CF₃, k) —NO₂, l) —NR²R², m) —C(O)NR²R², n)        —NR²R², o) —NR²(SO₂R⁶), p) —SO₂NR²R², q) —S(O)_(r)R⁶, r)        —CH═N—R⁴⁰, s) —CH(OH)—SO₃R⁴¹, t) C₁₋₆ alkyl, u) C₂₋₆ alkenyl, v)        C₂₋₆ alkynyl, w) C₁₋₆ alkoxy, x) —C(O)—C₁₋₆ alkyl, y) C₁₋₆        alkylthio, z) C₁₋₆ acyl, aa) C₂₋₈ alkenylphenyl, bb) aryl,        and cc) heteroaryl,        -   wherein any of s)–bb) optionally is substituted with —OH,            —N₃, C₁₋₅ alkoxy, C₁₋₅ acyl, —NR²R², —SR⁴², —SO₂R⁶, or

R⁴⁰ is —OH, —OCH₂-aryl, —NHC(O)NH₂, —NHC(S)NH₂, or —NHC(═NH)NR²R²;

R⁴¹ is hydrogen or a sodium ion;

R⁴² is selected from the group consisting of:

R⁴³ is selected from the group consisting of:

-   -   a) C₁₋₈ alkyl, b) C₃₋₆ cycloalkyl, c) aryl, d) heteroaryl, e)        pyridyl, and f)

-   -   wherein        -   any of a)–f) optionally is substituted with one or more R¹³            groups, and L′ is O, CH₂, or NR²;

R⁴⁴, at each occurrence, independently is selected from the groupconsisting of:

-   -   a) hydrogen, b) C₃₋₆ cycloalkyl, c) C₁₋₆ acyl, d) C₁₋₈ alkyl, e)        C₁₋₆ alkoxy, f) heteroaryl, g) aryl,

-   -   wherein        -   any of b)–g) optionally is substituted with one or more R¹³            groups, or

and

-   -   -   L′ is O, CH₂, or NR²;

R⁴⁵ is —OH, C₁₋₄ alkoxy, or —NR²R²;

R⁴⁶ is hydrogen or a C₁₋₈ alkyl group optionally substituted with one ormoieties selected from the group consisting of indolyl, —OR³, —SR³,imidazolyl, C₁₋₈ alkylthio, —NR²R², and aryl,

-   -   wherein the aryl group optionally is substituted with OH,        —C(O)NH₂, —CO₂H, or —C(═NH)NH₂;

R⁴⁷ is selected from the group consisting of:

-   -   a) C₁₋₁₆ alkyl, b) C₂₋₁₆ alkenyl, c) aryl, and d) heteroaryl,        -   wherein any of a)–d) optionally is substituted with one or            more R¹³ groups;

R⁴⁸ is selected from the group consisting of:

-   -   —OH, —OCH₃, —NH₂, —OC(O)OCH₃, —OC(O)CH₂OC(O)CH₃, —O(CH₂)₂OH,        —OC(O)CH₂OCH₂C₆H₅, —O(CH₂)₂OCH₂OCH₃, and —OCH₂OCH₃;

R⁴⁹ is selected from the group consisting of:

-   -   hydrogen, —CH₂OH, and —CH₂OCH₂OCH₃;

R⁵⁰, at each occurrence, independently is hydrogen or CH₃;

alternatively, two R⁵⁰ groups taken together with the carbon atom towhich each is bonded are —CH₂CH₂—;

R⁵¹ is selected from the group consisting of:

-   -   a) hydrogen, b) C₁₋₆ alkyl, optionally substituted with one or        more hydroxyl groups, halogens, or —CN, c) —(CH₂)_(s)-aryl, d)        —CO₂R⁵², e) —COR⁵³, f) —C(O)(CH₂)_(s)C(O)R⁵², g) —S(O)₂C₁₋₆        alkyl, h) —S(O)₂(CH₂)_(s)-aryl, and i) —(C(O))_(s)-Het;

R⁵² is selected from the group consisting of:

-   -   a) hydrogen, b) C₁₋₆ alkyl, optionally substituted with one or        more hydroxyl groups, halogens, or —CN, c) —CH₂)_(s)-aryl,        and d) —(CH₂)_(s)—OR⁵⁴;

R⁵³ is selected from the group consisting of:

-   -   a) C₁₋₆ alkyl, optionally substituted with one or more hydroxyl        groups, halogens, or —CN, b) —(CH₂)_(s)-aryl, and c)        —CH₂)_(s)—OR⁵⁴;

R⁵⁴ is selected from the group consisting of:

-   -   a) hydrogen, b) C₁₋₆ alkyl, c) —CH₂)_(s)-aryl, and d) —C(O)—C₁₋₆        alkyl,        -   wherein the aryl group is selected from the group consisting            of phenyl, pyridyl, and napthyl,            -   wherein each of the phenyl, pyridyl, and napthyl                optionally is substituted with one or more moeiteis from                the group consisting of F, Cl, Br, —CN, —OH, —SH, C₁₋₆                alkyl, C₁₋₆ alkoxy, and C₁₋₆ alkylthio; and

G is selected from the group consisting of

-   -   a) C₁₋₄ alkyl, b) C₅₋₈ alkyl, c) C₂₋₈ alkenyl, d) C₂₋₈        alkynyl, e) C₁₋₈ alkoxy, f) C₁₋₈ alkylthio, g) C₁₋₈ acyl, h)        saturated, unsaturated, or aromatic C₅₋₁₀ carbocycle, i)        saturated, unsaturated, or aromatic 5–10 membered heterocycle        containing one or more heteroatoms selected from the group        consisting of nitrogen, oxygen, and sulfur,

-   -   wherein        -   i) a) is substituted with, and        -   ii) any of b)–i) optionally is substituted with one or more            moieties selected from the group consisting of:            -   carbonyl; formyl; F; Cl; Br; I; CN; NO₂; OR³;                —S(O)_(r)R⁵; —S(O)_(r)N═R², —C(O)R²; —C(O)OR³; —OC(O)R²;                —C(O)NR²R²; —OC(O)NR²R²; —C(═NR¹²)R²; —C(R²)(R²)OR³;                —C(R²)(R²)OC(O)R²; —C(R²)(OR³)(CH₂)_(r)NR²R²; —NR²R²;                —NR²OR³; —NR²C(O)R²; —NR²C(O)OR³; —NR²C(O)N²R²;                —NR²S(O)_(r)R⁵; —C(OR⁶)(OR⁶)R²; —C(R²)(R³)NR²R²;                —C(R²)(R³)NR²R¹²; ═NR¹²; —C(S)NR²R²; —NR²C(S)R²;                —OC(S)NR²R²; —NR²C(S)OR³; —NR²C(S)NR²R²; —SC(O)R²; C₂₋₅                alkenyl; C₂₋₅ alkynyl; C₁₋₈ alkoxy; C₁₋₈ alkylthio; C₁₋₈                acyl; saturated, unsaturated, or aromatic C₅₋₁₀                carbocycle, optionally substituted with one or more R¹³                groups; and saturated, unsaturated, or aromatic 5–10                membered heterocycle containing one or more heteroatoms                selected from the group consisting of nitrogen, oxygen,                and sulfur, and optionally substituted with one or more                R¹³ groups;

t, at each occurrence, independently is 0, 1, 2, or 3;

v is 0, 1, 2, 3, 4, 5, or 6;

K′ is O, NR², or S(O)_(r);

R⁵⁵, at each occurrence, independently is hydrogen, —CH₂OH, or C₁₋₄alkyl;

alternatively, two R⁵⁵ groups taken together are a carbonyl group;

R¹⁴ is selected from the group consisting of:

-   -   a) hydrogen, b) C₁₋₆-alkyl, c) C₂₋₆ alkenyl, d) C₂₋₆ alkynyl, e)        —C(O)—R³, f) —C(O)—C₁₋₆ alkyl-R³, g) —C(O)—C₂₋₆ alkenyl-R³, h)        —C(O)—C₂₋₆ alkynyl-R³, i) —C₁₋₆ alkyl-J-R³, j) —C₂₋₆        alkenyl-J-R³; and k) —C₂₋₆ alkynyl-J-R³;    -   wherein        -   (i) any of b)–d) optionally is substituted with one or more            substituents selected from the group consisting of:            -   F, Cl, Br, I, aryl, substituted aryl, heteroaryl,                substituted heteroaryl, —OR³, —O—C₁₋₆ alkyl-R², —O—C₂₋₆                alkenyl-R², —O—C₂₋₆ alkynyl-R², and —NR²R²; and        -   (ii) J is selected from the group consisting of:            -   —OC(O)—, —OC(O)O—, —OC(O)NR²—, —C(O)NR²—, —NR²C(O)—,                —NR²C(O)O—, —NR²C(O)NR²—, —NR²C(NH)NR²—, and S(O)_(r);                and

R¹⁵ is selected from the group consisting of:

-   -   hydrogen; C₁₋₁₀ alkyl, optionally substituted with one or more        R¹³ groups; C₁₋₆ acyl, optionally substituted with one or more        R¹³ groups; aryl; substituted aryl; heteroaryl; substituted        heteroaryl; arylalkyl; substituted arylalkyl; and a macrolide;        -   wherein the macrolide is selected from the group consisting            of:

and pharmaceutically acceptable salts, esters and prodrugs thereof,wherein

R¹⁷ is selected from the group consisting of:

-   -   hydrogen, hydroxy protecting group, R³, and -V-W-R¹³,        -   wherein            -   V is —C(O), —C(O)O—, —C(O)NR²—, or absent, and            -   W is C₁₋₆ alkyl, or absent;

alternatively R¹⁷ and R¹⁴, taken together with the atoms to which theyare bonded, form:

Q is selected from the group consisting of:

-   -   —NR²CH₂—, —CH₂—NR²—, —C(O)—, —C(═NR²)—, —C(═NOR³)—,        —C(═N—NR²R²)—, —CH(OR³)—, and —CH(NR²R²)—;

R¹⁸ is selected from the group consisting of:

-   -   i) C₁₋₆ alkyl, ii) C₂₋₆ alkenyl, and iii) C₂₋₆ alkynyl;        -   wherein any of i)–iii) optionally is substituted with one or            more moieties selected from the group consisting of —OR³,            aryl, substituted aryl, heteroaryl, and substituted            heteroaryl;

R¹⁹ is selected from the group consisting of:

-   -   a) —OR¹⁷, b) C₁₋₆ alkyl, c) C₂₋₆alkenyl, d) C₂₋₆ alkynyl, e)        —NR²R², f) —C(O)R³, g) —C(O)—C₁₋₆ alkyl-R¹³, h) —C(O)—C₂₋₆        alkenyl-R¹³, and i) —C(O)—C₂₋₆ alkynyl-R¹³,        -   wherein any of b)–d) optionally is substituted with one or            more R¹³ groups;

alternatively, R¹⁴ and R¹⁹, taken together with the atoms to which theyare bonded, form:

-   -   wherein        -   L is CH or N, and        -   R²³ is —OR³, or R³;

R²⁰ is —OR¹⁷;

alternatively, R¹⁹ and R²⁰, taken together with the atoms to which theyare bonded, form a 5-membered ring by attachment to each other through alinker selected from the group consisting of:

-   -   —OC(R²)(R²)O—, —OC(O)O—, —OC(O)NR²—, —NR²C(O)O—, —OC(O)NOR³—,        —N(OR³)C(O)O—, —OC(O)N—NR²R²—, —N(NR²R²)C(O)O—, —OC(O)CHR²—,        —CHR²C(O)O—, —OC(S)O—, —OC(S)NR²—, —NR²C(S)O—, —OC(S)NOR³—,        —N(OR³)C(S)O—, —OC(S)N—NR²R²—, —N(NR²R²)C(S)O—, —OC(S)CHR²—, and        —CHR²C(S)O—;

alternatively, Q, R¹⁹, and R²⁰, taken together with the atoms to whichthey are bonded, form:

-   -   wherein        -   M is O or NR²;

R²¹ is selected from the group consisting of:

-   -   hydrogen, F, Cl, Br, I, and C₁₋₆ alkyl;

R²², at each occurrence, independently is selected from the groupconsisting of:

-   -   hydrogen, —OR³, —O-hydroxy protecting group, —O—C₁₋₆        alkyl-J-R¹³, —O—C₂₋₆ alkenyl-J-R¹³, —O—C₁₋₆ alkynyl-J-R¹³, and        —NR²R²;

alternatively, two R²² groups taken together are ═O, ═N—OR³, or═N—NR²R²; and

-   -   R², R³, R¹³, R¹⁴, and J are as described hereinabove.

Examples of:

include, but are not limited to, thiophene, furan, 4-oxo-2-imidazolyl,2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl,4-oxazolyl, 4-oxo-2-oxazolyl, 5-oxazolyl, 4,5,-dihydrooxazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole,5-isothiazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,5-oxo-1,2,4-oxadiazol-3-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, 3-oxo-1,2,4-thiadiazol-5-yl,1,3,4-thiadiazol-5-yl, 2-oxo-1,3,4-thiadiazol-5-yl, 1,2,3-triazol-1-yl,1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl,1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1-tetrazol-5-yl,2-tetrazol-5-yl, 3-isothiazolyl, 4-isothiazolyl and 5-isothiazolyl,4-oxo-2-thiazolinyl, or 5-methyl-1,3,4-thiadiazol-2-yl,thiazolidine-2,4-dione, oxazolidine-2,4-dione, imidazolidine-2,4-dione,oxazolidin-2-one, thiazolidin-2-one, 3H-oxazol-2-one,1,3-dihydro-imidazol-2-one, 1,3-dihydro-imidazole-2-thione,2-thioxo-imidazolidin-4-one, and 4-thioxo-imidazolidin-2-one.

In certain embodiments, the invention provides compounds having theformula:

-   -   wherein        -   A, at each occurrence, independently is carbon or nitrogen,            provided at least one A is carbon, and        -   p, q, B, D, E, and G are as defined hereinabove.

Other embodiments of the invention include compounds having the formula:

wherein

-   -   Y is oxygen or sulfur,    -   A, at each occurrence, independently is carbon or nitrogen, and    -   p, q, B, D, E, and G are as defined hereinabove.

In other embodiments, the invention provides compounds having theformula:

-   -   wherein p, q, A, B, E, and G are as defined hereinabove.

Features of these embodiments include compounds having the formula:

-   -   wherein A, E, and G are as defined hereinabove.

In some embodiments, the invention provides compounds having theformula:

-   -   wherein p, q, A, E, and G are as defined hereinabove.

Features of these embodiments include compounds having the formula:

-   -   wherein A, E, and G are as defined hereinabove.

In certain embodiments, E has the formula:

-   -   wherein R⁹ and R¹⁰, at each occurrence, are as defined        hereinabove.

Features of this embodiment include compounds wherein E has the formula:

Other features of this embodiment include compounds wherein R¹⁰ has theformula:

-   -   wherein K is selected from the group consisting of O, NR², and        S(O)_(r), and    -   x is 0, 1, 2, or 3.

In certain features of this embodiment, K is oxygen, and in otherfeatures, t is 1.

Still other features of this embodiment include compounds wherein R¹⁰ is—C(O)CH₃.

Yet another feature of this embodiment includes compounds wherein R¹⁰has the formula:

-   -   wherein R² and R⁷ are as defined hereinabove.

Certain other features of this embodiment include compounds wherein R²is —C(O)—CH₂—OH. In other features, R⁷ is hydrogen.

In other embodiments according to the invention, in the foregoingcompounds, G has the formula:

-   -   wherein R¹⁵ is a macrolide.

In other embodiments of the invention, G has the formula selected fromthe group consisting of:

and R¹⁵ is selected from the group consisting of:

In another embodiments according to the invention, in the foregoingcompounds, G has the formula:

wherein n is 1, 2, 3, or 4.

In still other embodiments, the invention provides compounds having theformula:

wherein G is as described hereinabove. Features of this embodimentinclude compounds wherein G is selected from the group consisting of.

Other embodiments of the invention include compounds having the formulaselected from:

or a pharmaceutically acceptable salt, ester, or prodrug thereof.

In another aspect, the invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of one or more of theforegoing compounds and a pharmaceutically acceptable carrier. In yetanother aspect, the invention provides a method for treating a microbialinfection, a fungal infection, a viral infection, a parasitic disease, aproliferative disease, an inflammatory disease, or a gastrointestinalmotility disorder in a mammal by administering effective amounts of thecompounds of the invention or pharmaceutical compositions of theinvention, for example, via oral, parenteral or topical routes. In stillanother aspect, the invention provides methods for synthesizing any oneof the foregoing compounds. In another aspect, the invention provides amedical device, for example, a medical stent, which contains or iscoated with one or more of the foregoing compounds.

In another embodiment, the invention further provides a family of hybridantibiotics comprising a heterocyclic side-chain linked via aheterocyclic linker to at least a portion of a macrolide-basedantibiotic. Exemplary heterocyclic side-chains, heterocylic linkers, andmacrolides useful in the synthesis of the hybrid antibiotics include,but are not limited to, the chemical moieties shown below:

Heterocyclic Side-chains

Heterocyclic Linkers

For the above heterocyclic linkers, it should be understood that “O” and“M” are included to depict the orientation of the heterocyclic linkerwith respect to the other structures that define the compounds of theinvention. More specifically, “O” denotes the portion of the compoundthat includes the heterocyclic side-chain moiety, and “M” denotes theportion of the compound that includes the macrolide moiety.

Macrolides

An exemplary scheme showing the linkage of a heterocyclic side-chain toa macrolide via a heterocyclic linker is shown below, where n can be 1,2, 3, or 4:

The various heterocyclic side-chains may be linked via the heterocycliclinkers to the macrolides using conventional chemistries known in theart, such as those discussed below. By using the various combinations ofchemical moieties provided, the skilled artisan may synthesize one ormore of the exemplary compounds listed in Table 1. For each set ofexamples, the four lower case letter designations denote three compoundswhere n=1, 2, 3, or 4. For example, as a guide to the following table,compound E1a is the n=1 variant of the structure shown on the same rowof the table. Compound E1b is the n=2 derivative, compound E1c is then=3 derivative, and E1d is the n=4 derivative.

TABLE 1 Example O Group H Group M Group E1a-d O1 H1 M1 E2a-d O1 H2 M1E3a-d O1 H3 M1 E4a-d O1 H4 M1 E5a-d O1 H5 M1 E6a-d O1 H6 M1 E7a-d O1 H7M1 E8a-d O1 H8 M1 E9a-d O1 H9 M1 E10a-d O2 H1 M1 E11a-d O2 H2 M1 E12a-dO2 H3 M1 E13a-d O2 H4 M1 E14a-d O2 H5 M1 E15a-d O2 H6 M1 E16a-d O2 H7 M1E17a-d O2 H8 M1 E18a-d O2 H9 M1 E19a-d O3 H1 M1 E20a-d O3 H2 M1 E21a-dO3 H3 M1 E22a-d O3 H4 M1 E23a-d O3 H5 M1 E24a-d O3 H6 M1 E25a-d O3 H7 M1E26a-d O3 H8 M1 E27a-d O3 H9 M1 E28a-d O4 H1 M1 E29a-d O4 H2 M1 E30a-dO4 H3 M1 E31a-d O4 H4 M1 E32a-d O4 H5 M1 E33a-d O4 H6 M1 E34a-d O4 H7 M1E35a-d O4 H8 M1 E36a-d O4 H9 M1 E37a-d O5 H1 M1 E38a-d O5 H2 M1 E39a-dO5 H3 M1 E40a-d O5 H4 M1 E41a-d O5 H5 M1 E42a-d O5 H6 M1 E43a-d O5 H7 M1E44a-d O5 H8 M1 E45a-d O5 H9 M1 E46a-d O6 H1 M1 E47a-d O6 H2 M1 E48a-dO6 H3 M1 E49a-d O6 H4 M1 E50a-d O6 H5 M1 E51a-d O6 H6 M1 E52a-d O6 H7 M1E53a-d O6 H8 M1 E54a-d O6 H9 M1 E55a-d O7 H1 M1 E56a-d O7 H2 M1 E57a-dO7 H3 M1 E58a-d O7 H4 M1 E59a-d O7 H5 M1 E60a-d O7 H6 M1 E61a-d O7 H7 M1E62a-d O7 H8 M1 E63a-d O7 H9 M1 E64a-d O8 H1 M1 E65a-d O8 H2 M1 E66a-dO8 H3 M1 E67a-d O8 H4 M1 E68a-d O8 H5 M1 E69a-d O8 H6 M1 E70a-d O8 H7 M1E71a-d O8 H8 M1 E72a-d O8 H9 M1 E73a-d O9 H1 M1 E74a-d O9 H2 M1 E75a-dO9 H3 M1 E76a-d O9 H4 M1 E77a-d O9 H5 M1 E78a-d O9 H6 M1 E79a-d O9 H7 M1E80a-d O9 H8 M1 E81a-d O9 H9 M1 E82a-d O10 H1 M1 E83a-d O10 H2 M1 E84a-dO10 H3 M1 E85a-d O10 H4 M1 E86a-d O10 H5 M1 E87a-d O10 H6 M1 E88a-d O10H7 M1 E89a-d O10 H8 M1 E90a-d O10 H9 M1 E91a-d O11 H1 M1 E92a-d O11 H2M1 E93a-d O11 H3 M1 E94a-d O11 H4 M1 E95a-d O11 H5 M1 E96a-d O11 H6 M1E97a-d O11 H7 M1 E98a-d O11 H8 M1 E99a-d O11 H9 M1 E100a-d O12 H1 M1E101a-d O12 H2 M1 E102a-d O12 H3 M1 E103a-d O12 H4 M1 E104a-d O12 H5 M1E105a-d O12 H6 M1 E106a-d O12 H7 M1 E107a-d O12 H8 M1 E108a-d O12 H9 M1E109a-d O13 H1 M1 E110a-d O13 H2 M1 E111a-d O13 H3 M1 E112a-d O13 H4 M1E113a-d O13 H5 M1 E114a-d O13 H6 M1 E115a-d O13 H7 M1 E116a-d O13 H8 M1E117a-d O13 H9 M1 E118a-d O14 H1 M1 E119a-d O14 H2 M1 E120a-d O14 H3 M1E121a-d O14 H4 M1 E122a-d O14 H5 M1 E123a-d O14 H6 M1 E124a-d O14 H7 M1E125a-d O14 H8 M1 E126a-d O14 H9 M1 E127a-d O15 H1 M1 E128a-d O15 H2 M1E129a-d O15 H3 M1 E130a-d O15 H4 M1 E131a-d O15 H5 M1 E132a-d O15 H6 M1E133a-d O15 H7 M1 E134a-d O15 H8 M1 E135a-d O15 H9 M1 E136a-d O16 H1 M1E137a-d O16 H2 M1 E138a-d O16 H3 M1 E139a-d O16 H4 M1 E140a-d O16 H5 M1E141a-d O16 H6 M1 E142a-d O16 H7 M1 E143a-d O16 H8 M1 E144a-d O16 H9 M1E145a-d O1 H1 M2 E146a-d O1 H2 M2 E147a-d O1 H3 M2 E148a-d O1 H4 M2E149a-d O1 H5 M2 E150a-d O1 H6 M2 E151a-d O1 H7 M2 E152a-d O1 H8 M2E153a-d O1 H9 M2 E154a-d O2 H1 M2 E155a-d O2 H2 M2 E156a-d O2 H3 M2E157a-d O2 H4 M2 E158a-d O2 H5 M2 E159a-d O2 H6 M2 E160a-d O2 H7 M2E161a-d O2 H8 M2 E162a-d O2 H9 M2 E163a-d O3 H1 M2 E164a-d O3 H2 M2E165a-d O3 H3 M2 E166a-d O3 H4 M2 E167a-d O3 H5 M2 E168a-d O3 H6 M2E169a-d O3 H7 M2 E170a-d O3 H8 M2 E171a-d O3 H9 M2 E172a-d O4 H1 M2E173a-d O4 H2 M2 E174a-d O4 H3 M2 E175a-d O4 H4 M2 E176a-d O4 H5 M2E177a-d O4 H6 M2 E178a-d O4 H7 M2 E179a-d O4 H8 M2 E180a-d O4 H9 M2E181a-d O5 H1 M2 E182a-d O5 H2 M2 E183a-d O5 H3 M2 E184a-d O5 H4 M2E185a-d O5 H5 M2 E186a-d O5 H6 M2 E187a-d O5 H7 M2 E188a-d O5 H8 M2E189a-d O5 H9 M2 E190a-d O6 H1 M2 E191a-d O6 H2 M2 E192a-d O6 H3 M2E193a-d O6 H4 M2 E194a-d O6 H5 M2 E195a-d O6 H6 M2 E196a-d O6 H7 M2E197a-d O6 H8 M2 E198a-d O6 H9 M2 E199a-d O7 H1 M2 E200a-d O7 H2 M2E201a-d O7 H3 M2 E202a-d O7 H4 M2 E203a-d O7 H5 M2 E204a-d O7 H6 M2E205a-d O7 H7 M2 E206a-d O7 H8 M2 E207a-d O7 H9 M2 E208a-d O8 H1 M2E209a-d O8 H2 M2 E210a-d O8 H3 M2 E211a-d O8 H4 M2 E212a-d O8 H5 M2E213a-d O8 H6 M2 E214a-d O8 H7 M2 E215a-d O8 H8 M2 E216a-d O8 H9 M2E217a-d O9 H1 M2 E218a-d O9 H2 M2 E219a-d O9 H3 M2 E220a-d O9 H4 M2E221a-d O9 H5 M2 E222a-d O9 H6 M2 E223a-d O9 H7 M2 E224a-d O9 H8 M2E225a-d O9 H9 M2 E226a-d O10 H1 M2 E227a-d O10 H2 M2 E228a-d O10 H3 M2E229a-d O10 H4 M2 E230a-d O10 H5 M2 E231a-d O10 H6 M2 E232a-d O10 H7 M2E233a-d O10 H8 M2 E234a-d O10 H9 M2 E235a-d O11 H1 M2 E236a-d O11 H2 M2E237a-d O11 H3 M2 E238a-d O11 H4 M2 E239a-d O11 H5 M2 E240a-d O11 H6 M2E241a-d O11 H7 M2 E242a-d O11 H8 M2 E243a-d O11 H9 M2 E244a-d O12 H1 M2E245a-d O12 H2 M2 E246a-d O12 H3 M2 E247a-d O12 H4 M2 E248a-d O12 H5 M2E249a-d O12 H6 M2 E250a-d O12 H7 M2 E251a-d O12 H8 M2 E252a-d O12 H9 M2E253a-d O13 H1 M2 E254a-d O13 H2 M2 E255a-d O13 H3 M2 E256a-d O13 H4 M2E257a-d O13 H5 M2 E258a-d O13 H6 M2 E259a-d O13 H7 M2 E260a-d O13 H8 M2E261a-d O13 H9 M2 E262a-d O14 H1 M2 E263a-d O14 H2 M2 E264a-d O14 H3 M2E265a-d O14 H4 M2 E266a-d O14 H5 M2 E267a-d O14 H6 M2 E268a-d O14 H7 M2E269a-d O14 H8 M2 E270a-d O14 H9 M2 E271a-d O15 H1 M2 E272a-d O15 H2 M2E273a-d O15 H3 M2 E274a-d O15 H4 M2 E275a-d O15 H5 M2 E276a-d O15 H6 M2E277a-d O15 H7 M2 E278a-d O15 H8 M2 E279a-d O15 H9 M2 E280a-d O16 H1 M2E281a-d O16 H2 M2 E282a-d O16 H3 M2 E283a-d O16 H4 M2 E284a-d O16 H5 M2E285a-d O16 H6 M2 E286a-d O16 H7 M2 E287a-d O16 H8 M2 E288a-d O16 H9 M2E289a-d O1 H1 M3 E290a-d O1 H2 M3 E291a-d O1 H3 M3 E292a-d O1 H4 M3E293a-d O1 H5 M3 E294a-d O1 H6 M3 E295a-d O1 H7 M3 E296a-d O1 H8 M3E297a-d O1 H9 M3 E298a-d O2 H1 M3 E299a-d O2 H2 M3 E300a-d O2 H3 M3E301a-d O2 H4 M3 E302a-d O2 H5 M3 E303a-d O2 H6 M3 E304a-d O2 H7 M3E305a-d O2 H8 M3 E306a-d O2 H9 M3 E307a-d O3 H1 M3 E308a-d O3 H2 M3E309a-d O3 H3 M3 E310a-d O3 H4 M3 E311a-d O3 H5 M3 E312a-d O3 H6 M3E313a-d O3 H7 M3 E314a-d O3 H8 M3 E315a-d O3 H9 M3 E316a-d O4 H1 M3E317a-d O4 H2 M3 E318a-d O4 H3 M3 E319a-d O4 H4 M3 E320a-d O4 H5 M3E321a-d O4 H6 M3 E322a-d O4 H7 M3 E323a-d O4 H8 M3 E324a-d O4 H9 M3E325a-d O5 H1 M3 E326a-d O5 H2 M3 E327a-d O5 H3 M3 E328a-d O5 H4 M3E329a-d O5 H5 M3 E330a-d O5 H6 M3 E331a-d O5 H7 M3 E332a-d O5 H8 M3E333a-d O5 H9 M3 E334a-d O6 H1 M3 E335a-d O6 H2 M3 E336a-d O6 H3 M3E337a-d O6 H4 M3 E338a-d O6 H5 M3 E339a-d O6 H6 M3 E340a-d O6 H7 M3E341a-d O6 H8 M3 E342a-d O6 H9 M3 E343a-d O7 H1 M3 E344a-d O7 H2 M3E345a-d O7 H3 M3 E346a-d O7 H4 M3 E347a-d O7 H5 M3 E348a-d O7 H6 M3E349a-d O7 H7 M3 E350a-d O7 H8 M3 E351a-d O7 H9 M3 E352a-d O7 H1 M3E353a-d O8 H2 M3 E354a-d O8 H3 M3 E355a-d O8 H4 M3 E356a-d O8 H5 M3E357a-d O8 H6 M3 E358a-d O8 H7 M3 E359a-d O8 H8 M3 E360a-d O8 H9 M3E361a-d O9 H1 M3 E362a-d O9 H2 M3 E363a-d O9 H3 M3 E364a-d O9 H4 M3E365a-d O9 H5 M3 E366a-d O9 H6 M3 E367a-d O9 H7 M3 E368a-d O9 H8 M3E369a-d O9 H9 M3 E370a-d O10 H1 M3 E371a-d O10 H2 M3 E372a-d O10 H3 M3E373a-d O10 H4 M3 E374a-d O10 H5 M3 E375a-d O10 H6 M3 E376a-d O10 H7 M3E377a-d O10 H8 M3 E378a-d O10 H9 M3 E379a-d O11 H1 M3 E380a-d O11 H2 M3E381a-d O11 H3 M3 E382a-d O11 H4 M3 E383a-d O11 H5 M3 E384a-d O11 H6 M3E385a-d O11 H7 M3 E386a-d O11 H8 M3 E387a-d O11 H9 M3 E388a-d O12 H1 M3E389a-d O12 H2 M3 E390a-d O12 H3 M3 E391a-d O12 H4 M3 E392a-d O12 H5 M3E393a-d O12 H6 M3 E394a-d O12 H7 M3 E395a-d O12 H8 M3 E396a-d O12 H9 M3E397a-d O13 H1 M3 E398a-d O13 H2 M3 E399a-d O13 H3 M3 E400a-d O13 H4 M3E401a-d O13 H5 M3 E402a-d O13 H6 M3 E403a-d O13 H7 M3 E404a-d O13 H8 M3E405a-d O13 H9 M3 E406a-d O14 H1 M3 E407a-d O14 H2 M3 E408a-d O14 H3 M3E409a-d O14 H4 M3 E410a-d O14 H5 M3 E411a-d O14 H6 M3 E412a-d O14 H7 M3E413a-d O14 H8 M3 E414a-d O14 H9 M3 E415a-d O15 H1 M3 E416a-d O15 H2 M3E417a-d O15 H3 M3 E418a-d O15 H4 M3 E419a-d O15 H5 M3 E420a-d O15 H6 M3E421a-d O15 H7 M3 E422a-d O15 H8 M3 E423a-d O15 H9 M3 E424a-d O16 H1 M3E425a-d O16 H2 M3 E426a-d O16 H3 M3 E427a-d O16 H4 M3 E428a-d O16 H5 M3E429a-d O16 H6 M3 E430a-d O16 H7 M3 E431a-d O16 H8 M3 E432a-d O16 H9 M3E433a-d O1 H1 M4 E434a-d O1 H2 M4 E435a-d O1 H3 M4 E436a-d O1 H4 M4E437a-d O1 H5 M4 E438a-d O1 H6 M4 E439a-d O1 H7 M4 E440a-d O1 H8 M4E441a-d O1 H9 M4 E442a-d O2 H1 M4 E443a-d O2 H2 M4 E444a-d O2 H3 M4E445a-d O2 H4 M4 E446a-d O2 H5 M4 E447a-d O2 H6 M4 E448a-d O2 H7 M4E449a-d O2 H8 M4 E450a-d O2 H9 M4 E451a-d O3 H1 M4 E452a-d O3 H2 M4E453a-d O3 H3 M4 E454a-d O3 H4 M4 E455a-d O3 H5 M4 E456a-d O3 H6 M4E457a-d O3 H7 M4 E458a-d O3 H8 M4 E459a-d O3 H9 M4 E460a-d O4 H1 M4E461a-d O4 H2 M4 E462a-d O4 H3 M4 E463a-d O4 H4 M4 E464a-d O4 H5 M4E465a-d O4 H6 M4 E466a-d O4 H7 M4 E467a-d O4 H8 M4 E468a-d O4 H9 M4E469a-d O5 H1 M4 E470a-d O5 H2 M4 E471a-d O5 H3 M4 E472a-d O5 H4 M4E473a-d O5 H5 M4 E474a-d O5 H6 M4 E475a-d O5 H7 M4 E476a-d O5 H8 M4E477a-d O5 H9 M4 E478a-d O6 H1 M4 E479a-d O6 H2 M4 E480a-d O6 H3 M4E481a-d O6 H4 M4 E482a-d O6 H5 M4 E483a-d O6 H6 M4 E484a-d O6 H7 M4E485a-d O6 H8 M4 E486a-d O6 H9 M4 E487a-d O7 H1 M4 E488a-d O7 H2 M4E489a-d O7 H3 M4 E490a-d O7 H4 M4 E491a-d O7 H5 M4 E492a-d O7 H6 M4E493a-d O7 H7 M4 E494a-d O7 H8 M4 E495a-d O7 H9 M4 E496a-d O8 H1 M4E497a-d O8 H2 M4 E498a-d O8 H3 M4 E499a-d O8 H4 M4 E500a-d O8 H5 M4E501a-d O8 H6 M4 E502a-d O8 H7 M4 E503a-d O8 H8 M4 E504a-d O8 H9 M4E505a-d O9 H1 M4 E506a-d O9 H2 M4 E507a-d O9 H3 M4 E508a-d O9 H4 M4E509a-d O9 H5 M4 E510a-d O9 H6 M4 E511a-d O9 H7 M4 E512a-d O9 H8 M4E513a-d O9 H9 M4 E514a-d O10 H1 M4 E515a-d O10 H2 M4 E516a-d O10 H3 M4E517a-d O10 H4 M4 E518a-d O10 H5 M4 E519a-d O10 H6 M4 E520a-d O10 H7 M4E521a-d O10 H8 M4 E522a-d O10 H9 M4 E523a-d O11 H1 M4 E524a-d O11 H2 M4E525a-d O11 H3 M4 E526a-d O11 H4 M4 E527a-d O11 H5 M4 E528a-d O11 H6 M4E529a-d O11 H7 M4 E530a-d O11 H8 M4 E531a-d O11 H9 M4 E532a-d O12 H1 M4E533a-d O12 H2 M4 E534a-d O12 H3 M4 E535a-d O12 H4 M4 E536a-d O12 H5 M4E537a-d O12 H6 M4 E538a-d O12 H7 M4 E539a-d O12 H8 M4 E540a-d O12 H9 M4E541a-d O13 H1 M4 E542a-d O13 H2 M4 E543a-d O13 H3 M4 E544a-d O13 H4 M4E545a-d O13 H5 M4 E546a-d O13 H6 M4 E547a-d O13 H7 M4 E548a-d O13 H8 M4E549a-d O13 H9 M4 E550a-d O14 H1 M4 E551a-d O14 H2 M4 E552a-d O14 H3 M4E553a-d O14 H4 M4 E554a-d O14 H5 M4 E555a-d O14 H6 M4 E556a-d O14 H7 M4E557a-d O14 H8 M4 E558a-d O14 H9 M4 E559a-d O15 H1 M4 E560a-d O15 H2 M4E561a-d O15 H3 M4 E562a-d O15 H4 M4 E563a-d O15 H5 M4 E564a-d O15 H6 M4E565a-d O15 H7 M4 E566a-d O15 H8 M4 E567a-d O15 H9 M4 E568a-d O16 H1 M4E569a-d O16 H2 M4 E570a-d O16 H3 M4 E571a-d O16 H4 M4 E572a-d O16 H5 M4E573a-d O16 H6 M4 E574a-d O16 H7 M4 E575a-d O16 H8 M4 E576a-d O16 H9 M4E577a-d O1 H1 M5 E578a-d O1 H2 M5 E579a-d O1 H3 M5 E580a-d O1 H4 M5E581a-d O1 H5 M5 E582a-d O1 H6 M5 E583a-d O1 H7 M5 E584a-d O1 H8 M5E585a-d O1 H9 M5 E586a-d O2 H1 M5 E587a-d O2 H2 M5 E588a-d O2 H3 M5E589a-d O2 H4 M5 E590a-d O2 H5 M5 E591a-d O2 H6 M5 E592a-d O2 H7 M5E593a-d O2 H8 M5 E594a-d O2 H9 M5 E595a-d O3 H1 M5 E596a-d O3 H2 M5E597a-d O3 H3 M5 E598a-d O3 H4 M5 E599a-d O3 H5 M5 E600a-d O3 H6 M5E601a-d O3 H7 M5 E602a-d O3 H8 M5 E603a-d O3 H9 M5 E604a-d O4 H1 M5E605a-d O4 H2 M5 E606a-d O4 H3 M5 E607a-d O4 H4 M5 E608a-d O4 H5 M5E609a-d O4 H6 M5 E610a-d O4 H7 M5 E611a-d O4 H8 M5 E612a-d O4 H9 M5E613a-d O5 H1 M5 E614a-d O5 H2 M5 E615a-d O5 H3 M5 E616a-d O5 H4 M5E617a-d O5 H5 M5 E618a-d O5 H6 M5 E619a-d O5 H7 M5 E620a-d O5 H8 M5E621a-d O5 H9 M5 E622a-d O6 H1 M5 E623a-d O6 H2 M5 E624a-d O6 H3 M5E625a-d O6 H4 M5 E626a-d O6 H5 M5 E627a-d O6 H6 M5 E628a-d O6 H7 M5E629a-d O6 H8 M5 E630a-d O6 H9 M5 E631a-d O7 H1 M5 E632a-d O7 H2 M5E633a-d O7 H3 M5 E634a-d O7 H4 M5 E635a-d O7 H5 M5 E636a-d O7 H6 M5E637a-d O7 H7 M5 E638a-d O7 H8 M5 E639a-d O7 H9 M5 E640a-d O8 H1 M5E641a-d O8 H2 M5 E642a-d O8 H3 M5 E643a-d O8 H4 M5 E644a-d O8 H5 M5E645a-d O8 H6 M5 E646a-d O8 H7 M5 E647a-d O8 H8 M5 E648a-d O8 H9 M5E649a-d O9 H1 M5 E650a-d O9 H2 M5 E651a-d O9 H3 M5 E652a-d O9 H4 M5E653a-d O9 H5 M5 E654a-d O9 H6 M5 E655a-d O9 H7 M5 E656a-d O9 H8 M5E657a-d O9 H9 M5 E658a-d O10 H1 M5 E659a-d O10 H2 M5 E660a-d O10 H3 M5E661a-d O10 H4 M5 E662a-d O10 H5 M5 E663a-d O10 H6 M5 E664a-d O10 H7 M5E665a-d O10 H8 M5 E666a-d O10 H9 M5 E667a-d O11 H1 M5 E668a-d O11 H2 M5E669a-d O11 H3 M5 E670a-d O11 H4 M5 E671a-d O11 H5 M5 E672a-d O11 H6 M5E673a-d O11 H7 M5 E674a-d O11 H8 M5 E675a-d O11 H9 M5 E676a-d O12 H1 M5E677a-d O12 H2 M5 E678a-d O12 H3 M5 E679a-d O12 H4 M5 E680a-d O12 H5 M5E681a-d O12 H6 M5 E682a-d O12 H7 M5 E683a-d O12 H8 M5 E684a-d O12 H9 M5E685a-d O13 H1 M5 E686a-d O13 H2 M5 E687a-d O13 H3 M5 E688a-d O13 H4 M5E689a-d O13 H5 M5 E690a-d O13 H6 M5 E691a-d O13 H7 M5 E692a-d O13 H8 M5E693a-d O13 H9 M5 E694a-d O14 H1 M5 E695a-d O14 H2 M5 E696a-d O14 H3 M5E697a-d O14 H4 M5 E698a-d O14 H5 M5 E699a-d O14 H6 M5 E700a-d O14 H7 M5E701a-d O14 H8 M5 E702a-d O14 H9 M5 E703a-d O15 H1 M5 E704a-d O15 H2 M5E705a-d O15 H3 M5 E706a-d O15 H4 M5 E707a-d O15 H5 M5 E708a-d O15 H6 M5E709a-d O15 H7 M5 E710a-d O15 H8 M5 E711a-d O15 H9 M5 E712a-d O16 H1 M5E713a-d O16 H2 M5 E714a-d O16 H3 M5 E715a-d O16 H4 M5 E716a-d O16 H5 M5E717a-d O16 H6 M5 E718a-d O16 H7 M5 E719a-d O16 H8 M5 E720a-d O16 H9 M5E721a-d O1 H1 M6 E722a-d O1 H2 M6 E723a-d O1 H3 M6 E724a-d O1 H4 M6E725a-d O1 H5 M6 E726a-d O1 H6 M6 E727a-d O1 H7 M6 E728a-d O1 H8 M6E729a-d O1 H9 M6 E730a-d O2 H1 M6 E731a-d O2 H2 M6 E732a-d O2 H3 M6E733a-d O2 H4 M6 E734a-d O2 H5 M6 E735a-d O2 H6 M6 E736a-d O2 H7 M6E737a-d O2 H8 M6 E738a-d O2 H9 M6 E739a-d O3 H1 M6 E740a-d O3 H2 M6E741a-d O3 H3 M6 E742a-d O3 H4 M6 E743a-d O3 H5 M6 E744a-d O3 H6 M6E745a-d O3 H7 M6 E746a-d O3 H8 M6 E747a-d O3 H9 M6 E748a-d O4 H1 M6E749a-d O4 H2 M6 E750a-d O4 H3 M6 E751a-d O4 H4 M6 E752a-d O4 H5 M6E753a-d O4 H6 M6 E754a-d O4 H7 M6 E755a-d O4 H8 M6 E756a-d O4 H9 M6E757a-d O5 H1 M6 E758a-d O5 H2 M6 E759a-d O5 H3 M6 E760a-d O5 H4 M6E761a-d O5 H5 M6 E762a-d O5 H6 M6 E763a-d O5 H7 M6 E764a-d O5 H8 M6E765a-d O5 H9 M6 E766a-d O6 H1 M6 E767a-d O6 H2 M6 E768a-d O6 H3 M6E769a-d O6 H4 M6 E770a-d O6 H5 M6 E771a-d O6 H6 M6 E772a-d O6 H7 M6E773a-d O6 H8 M6 E774a-d O6 H9 M6 E775a-d O7 H1 M6 E776a-d O7 H2 M6E777a-d O7 H3 M6 E778a-d O7 H4 M6 E779a-d O7 H5 M6 E780a-d O7 H6 M6E781a-d O7 H7 M6 E782a-d O7 H8 M6 E783a-d O7 H9 M6 E784a-d O8 H1 M6E785a-d O8 H2 M6 E786a-d O8 H3 M6 E787a-d O8 H4 M6 E788a-d O8 H5 M6E789a-d O8 H6 M6 E790a-d O8 H7 M6 E791a-d O8 H8 M6 E792a-d O8 H9 M6E793a-d O9 H1 M6 E794a-d O9 H2 M6 E795a-d O9 H3 M6 E796a-d O9 H4 M6E797a-d O9 H5 M6 E798a-d O9 H6 M6 E799a-d O9 H7 M6 E800a-d O9 H8 M6E801a-d O9 H9 M6 E802a-d O10 H1 M6 E803a-d O10 H2 M6 E804a-d O10 H3 M6E805a-d O10 H4 M6 E806a-d O10 H5 M6 E807a-d O10 H6 M6 E808a-d O10 H7 M6E809a-d O10 H8 M6 E810a-d O10 H9 M6 E811a-d O11 H1 M6 E812a-d O11 H2 M6E813a-d O11 H3 M6 E814a-d O11 H4 M6 E815a-d O11 H5 M6 E816a-d O11 H6 M6E817a-d O11 H7 M6 E818a-d O11 H8 M6 E819a-d O11 H9 M6 E820a-d O12 H1 M6E821a-d O12 H2 M6 E822a-d O12 H3 M6 E823a-d O12 H4 M6 E824a-d O12 H5 M6E825a-d O12 H6 M6 E826a-d O12 H7 M6 E827a-d O12 H8 M6 E828a-d O12 H9 M6E829a-d O13 H1 M6 E830a-d O13 H2 M6 E831a-d O13 H3 M6 E832a-d O13 H4 M6E833a-d O13 H5 M6 E834a-d O13 H6 M6 E835a-d O13 H7 M6 E836a-d O13 H8 M6E837a-d O13 H9 M6 E838a-d O14 H1 M6 E839a-d O14 H2 M6 E840a-d O14 H3 M6E841a-d O14 H4 M6 E842a-d O14 H5 M6 E843a-d O14 H6 M6 E844a-d O14 H7 M6E845a-d O14 H8 M6 E846a-d O14 H9 M6 E847a-d O15 H1 M6 E848a-d O15 H2 M6E849a-d O15 H3 M6 E850a-d O15 H4 M6 E851a-d O15 H5 M6 E852a-d O15 H6 M6E853a-d O15 H7 M6 E854a-d O15 H8 M6 E855a-d O15 H9 M6 E856a-d O16 H1 M6E857a-d O16 H2 M6 E858a-d O16 H3 M6 E859a-d O16 H4 M6 E860a-d O16 H5 M6E861a-d O16 H6 M6 E862a-d O16 H7 M6 E863a-d O16 H8 M6 E864a-d O16 H9 M6E865a-d O1 H1 M7 E866a-d O1 H2 M7 E867a-d O1 H3 M7 E868a-d O1 H4 M7E869a-d O1 H5 M7 E870a-d O1 H6 M7 E871a-d O1 H7 M7 E872a-d O1 H8 M7E873a-d O1 H9 M7 E874a-d O2 H1 M7 E875a-d O2 H2 M7 E876a-d O2 H3 M7E877a-d O2 H4 M7 E878a-d O2 H5 M7 E879a-d O2 H6 M7 E880a-d O2 H7 M7E881a-d O2 H8 M7 E882a-d O2 H9 M7 E883a-d O3 H1 M7 E884a-d O3 H2 M7E885a-d O3 H3 M7 E886a-d O3 H4 M7 E887a-d O3 H5 M7 E888a-d O3 H6 M7E889a-d O3 H7 M7 E890a-d O3 H8 M7 E891a-d O3 H9 M7 E892a-d O4 H1 M7E893a-d O4 H2 M7 E894a-d O4 H3 M7 E895a-d O4 H4 M7 E896a-d O4 H5 M7E897a-d O4 H6 M7 E898a-d O4 H7 M7 E899a-d O4 H8 M7 E900a-d O4 H9 M7E901a-d O5 H1 M7 E902a-d O5 H2 M7 E903a-d O5 H3 M7 E904a-d O5 H4 M7E905a-d O5 H5 M7 E906a-d O5 H6 M7 E907a-d O5 H7 M7 E908a-d O5 H8 M7E909a-d O5 H9 M7 E910a-d O6 H1 M7 E911a-d O6 H2 M7 E912a-d O6 H3 M7E913a-d O6 H4 M7 E914a-d O6 H5 M7 E915a-d O6 H6 M7 E916a-d O6 H7 M7E917a-d O6 H8 M7 E918a-d O6 H9 M7 E919a-d O7 H1 M7 E920a-d O7 H2 M7E921a-d O7 H3 M7 E922a-d O7 H4 M7 E923a-d O7 H5 M7 E924a-d O7 H6 M7E925a-d O7 H7 M7 E926a-d O7 H8 M7 E927a-d O7 H9 M7 E928a-d O8 H1 M7E929a-d O8 H2 M7 E930a-d O8 H3 M7 E931a-d O8 H4 M7 E932a-d O8 H5 M7E933a-d O8 H6 M7 E934a-d O8 H7 M7 E935a-d O8 H8 M7 E936a-d O8 H9 M7E937a-d O9 H1 M7 E938a-d O9 H2 M7 E939a-d O9 H3 M7 E940a-d O9 H4 M7E941a-d O9 H5 M7 E942a-d O9 H6 M7 E943a-d O9 H7 M7 E944a-d O9 H8 M7E945a-d O9 H9 M7 E946a-d O10 H1 M7 E947a-d O10 H2 M7 E948a-d O10 H3 M7E949a-d O10 H4 M7 E950a-d O10 H5 M7 E951a-d O10 H6 M7 E952a-d O10 H7 M7E953a-d O10 H8 M7 E954a-d O10 H9 M7 E955a-d O11 H1 M7 E956a-d O11 H2 M7E957a-d O11 H3 M7 E958a-d O11 H4 M7 E959a-d O11 H5 M7 E960a-d O11 H6 M7E961a-d O11 H7 M7 E962a-d O11 H8 M7 E963a-d O11 H9 M7 E964a-d O12 H1 M7E965a-d O12 H2 M7 E966a-d O12 H3 M7 E967a-d O12 H4 M7 E968a-d O12 H5 M7E969a-d O12 H6 M7 E970a-d O12 H7 M7 E971a-d O12 H8 M7 E972a-d O12 H9 M7E973a-d O13 H1 M7 E974a-d O13 H2 M7 E975a-d O13 H3 M7 E976a-d O13 H4 M7E977a-d O13 H5 M7 E978a-d O13 H6 M7 E979a-d O13 H7 M7 E980a-d O13 H8 M7E981a-d O13 H9 M7 E982a-d O14 H1 M7 E983a-d O14 H2 M7 E984a-d O14 H3 M7E985a-d O14 H4 M7 E986a-d O14 H5 M7 E987a-d O14 H6 M7 E988a-d O14 H7 M7E989a-d O14 H8 M7 E990a-d O14 H9 M7 E991a-d O15 H1 M7 E992a-d O15 H2 M7E993a-d O15 H3 M7 E994a-d O15 H4 M7 E995a-d O15 H5 M7 E996a-d O15 H6 M7E997a-d O15 H7 M7 E998a-d O15 H8 M7 E999a-d O15 H9 M7 E1000a-d O16 H1 M7E1001a-d O16 H2 M7 E1002a-d O16 H3 M7 E1003a-d O16 H4 M7 E1004a-d O16 H5M7 E1005a-d O16 H6 M7 E1006a-d O16 H7 M7 E1007a-d O16 H8 M7 E1008a-d O16H9 M7 E1009a-d O1 H1 M8 E1010a-d O1 H2 M8 E1011a-d O1 H3 M8 E1012a-d O1H4 M8 E1013a-d O1 H5 M8 E1014a-d O1 H6 M8 E1015a-d O1 H7 M8 E1016a-d O1H8 M8 E1017a-d O1 H9 M8 E1018a-d O2 H1 M8 E1019a-d O2 H2 M8 E1020a-d O2H3 M8 E1021a-d O2 H4 M8 E1022a-d O2 H5 M8 E1023a-d O2 H6 M8 E1024a-d O2H7 M8 E1025a-d O2 H8 M8 E1026a-d O2 H9 M8 E1027a-d O3 H1 M8 E1028a-d O3H2 M8 E1029a-d O3 H3 M8 E1030a-d O3 H4 M8 E1031a-d O3 H5 M8 E1032a-d O3H6 M8 E1033a-d O3 H7 M8 E1034a-d O3 H8 M8 E1035a-d O3 H9 M8 E1036a-d O4H1 M8 E1037a-d O4 H2 M8 E1038a-d O4 H3 M8 E1039a-d O4 H4 M8 E1040a-d O4H5 M8 E1041a-d O4 H6 M8 E1042a-d O4 H7 M8 E1043a-d O4 H8 M8 E1044a-d O4H9 M8 E1045a-d O5 H1 M8 E1046a-d O5 H2 M8 E1047a-d O5 H3 M8 E1048a-d O5H4 M8 E1049a-d O5 H5 M8 E1050a-d O5 H6 M8 E1051a-d O5 H7 M8 E1052a-d O5H8 M8 E1053a-d O5 H9 M8 E1054a-d O6 H1 M8 E1055a-d O6 H2 M8 E1056a-d O6H3 M8 E1057a-d O6 H4 M8 E1058a-d O6 H5 M8 E1059a-d O6 H6 M8 E1060a-d O6H7 M8 E1061a-d O6 H8 M8 E1062a-d O6 H9 M8 E1063a-d O7 H1 M8 E1064a-d O7H2 M8 E1065a-d O7 H3 M8 E1066a-d O7 H4 M8 E1067a-d O7 H5 M8 E1068a-d O7H6 M8 E1069a-d O7 H7 M8 E1070a-d O7 H8 M8 E1071a-d O7 H9 M8 E1072a-d O8H1 M8 E1073a-d O8 H2 M8 E1074a-d O8 H3 M8 E1075a-d O8 H4 M8 E1076a-d O8H5 M8 E1077a-d O8 H6 M8 E1078a-d O8 H7 M8 E1079a-d O8 H8 M8 E1080a-d O8H9 M8 E1081a-d O9 H1 M8 E1082a-d O9 H2 M8 E1083a-d O9 H3 M8 E1084a-d O9H4 M8 E1085a-d O9 H5 M8 E1086a-d O9 H6 M8 E1087a-d O9 H7 M8 E1088a-d O9H8 M8 E1089a-d O9 H9 M8 E1090a-d O10 H1 M8 E1091a-d O10 H2 M8 E1092a-dO10 H3 M8 E1093a-d O10 H4 M8 E1094a-d O10 H5 M8 E1095a-d O10 H6 M8E1096a-d O10 H7 M8 E1097a-d O10 H8 M8 E1098a-d O10 H9 M8 E1099a-d O11 H1M8 E1100a-d O11 H2 M8 E1101a-d O11 H3 M8 E1102a-d O11 H4 M8 E1103a-d O11H5 M8 E1104a-d O11 H6 M8 E1105a-d O11 H7 M8 E1106a-d O11 H8 M8 E1107a-dO11 H9 M8 E1108a-d O12 H1 M8 E1109a-d O12 H2 M8 E1110a-d O12 H3 M8E1111a-d O12 H4 M8 E1112a-d O12 H5 M8 E1113a-d O12 H6 M8 E1114a-d O12 H7M8 E1115a-d O12 H8 M8 E1116a-d O12 H9 M8 E1117a-d O13 H1 M8 E1118a-d O13H2 M8 E1119a-d O13 H3 M8 E1120a-d O13 H4 M8 E1121a-d O13 H5 M8 E1122a-dO13 H6 M8 E1123a-d O13 H7 M8 E1124a-d O13 H8 M8 E1125a-d O13 H9 M8E1126a-d O14 H1 M8 E1127a-d O14 H2 M8 E1128a-d O14 H3 M8 E1129a-d O14 H4M8 E1130a-d O14 H5 M8 E1131a-d O14 H6 M8 E1132a-d O14 H7 M8 E1133a-d O14H8 M8 E1134a-d O14 H9 M8 E1135a-d O15 H1 M8 E1136a-d O15 H2 M8 E1137a-dO15 H3 M8 E1138a-d O15 H4 M8 E1139a-d O15 H5 M8 E1140a-d O15 H6 M8E1141a-d O15 H7 M8 E1142a-d O15 H8 M8 E1143a-d O15 H9 M8 E1144a-d O16 H1M8 E1145a-d O16 H2 M8 E1146a-d O16 H3 M8 E1147a-d O16 H4 M8 E1148a-d O16H5 M8 E1149a-d O16 H6 M8 E1150a-d O16 H7 M8 E1151a-d O16 H8 M8 E1152a-dO16 H9 M8 E1153a-d O1 H1 M9 E1154a-d O1 H2 M9 E1155a-d O1 H3 M9 E1156a-dO1 H4 M9 E1157a-d O1 H5 M9 E1158a-d O1 H6 M9 E1159a-d O1 H7 M9 E1160a-dO1 H8 M9 E1161a-d O1 H9 M9 E1162a-d O2 H1 M9 E1163a-d O2 H2 M9 E1164a-dO2 H3 M9 E1165a-d O2 H4 M9 E1166a-d O2 H5 M9 E1167a-d O2 H6 M9 E1168a-dO2 H7 M9 E1169a-d O2 H8 M9 E1170a-d O2 H9 M9 E1171a-d O3 H1 M9 E1172a-dO3 H2 M9 E1173a-d O3 H3 M9 E1174a-d O3 H4 M9 E1175a-d O3 H5 M9 E1176a-dO3 H6 M9 E1177a-d O3 H7 M9 E1178a-d O3 H8 M9 E1179a-d O3 H9 M9 E1180a-dO4 H1 M9 E1181a-d O4 H2 M9 E1182a-d O4 H3 M9 E1183a-d O4 H4 M9 E1184a-dO4 H5 M9 E1185a-d O4 H6 M9 E1186a-d O4 H7 M9 E1187a-d O4 H8 M9 E1188a-dO4 H9 M9 E1189a-d O5 H1 M9 E1190a-d O5 H2 M9 E1191a-d O5 H3 M9 E1192a-dO5 H4 M9 E1193a-d O5 H5 M9 E1194a-d O5 H6 M9 E1195a-d O5 H7 M9 E1196a-dO5 H8 M9 E1197a-d O5 H9 M9 E1198a-d O6 H1 M9 E1199a-d O6 H2 M9 E1200a-dO6 H3 M9 E1201a-d O6 H4 M9 E1202a-d O6 H5 M9 E1203a-d O6 H6 M9 E1204a-dO6 H7 M9 E1205a-d O6 H8 M9 E1206a-d O6 H9 M9 E1207a-d O7 H1 M9 E1208a-dO7 H2 M9 E1209a-d O7 H3 M9 E1210a-d O7 H4 M9 E1211a-d O7 H5 M9 E1212a-dO7 H6 M9 E1213a-d O7 H7 M9 E1214a-d O7 H8 M9 E1215a-d O7 H9 M9 E1216a-dO8 H1 M9 E1217a-d O8 H2 M9 E1218a-d O8 H3 M9 E1219a-d O8 H4 M9 E1220a-dO8 H5 M9 E1221a-d O8 H6 M9 E1222a-d O8 H7 M9 E1223a-d O8 H8 M9 E1224a-dO8 H9 M9 E1225a-d O9 H1 M9 E1226a-d O9 H2 M9 E1227a-d O9 H3 M9 E1228a-dO9 H4 M9 E1229a-d O9 H5 M9 E1230a-d O9 H6 M9 E1231a-d O9 H7 M9 E1232a-dO9 H8 M9 E1233a-d O9 H9 M9 E1234a-d O10 H1 M9 E1235a-d O10 H2 M9E1236a-d O10 H3 M9 E1237a-d O10 H4 M9 E1238a-d O10 H5 M9 E1239a-d O10 H6M9 E1240a-d O10 H7 M9 E1241a-d O10 H8 M9 E1242a-d O10 H9 M9 E1243a-d O11H1 M9 E1244a-d O11 H2 M9 E1245a-d O11 H3 M9 E1246a-d O11 H4 M9 E1247a-dO11 H5 M9 E1248a-d O11 H6 M9 E1249a-d O11 H7 M9 E1250a-d O11 H8 M9E1251a-d O11 H9 M9 E1252a-d O12 H1 M9 E1253a-d O12 H2 M9 E1254a-d O12 H3M9 E1255a-d O12 H4 M9 E1256a-d O12 H5 M9 E1257a-d O12 H6 M9 E1258a-d O12H7 M9 E1259a-d O12 H8 M9 E1260a-d O12 H9 M9 E1261a-d O13 H1 M9 E1262a-dO13 H2 M9 E1263a-d O13 H3 M9 E1264a-d O13 H4 M9 E1265a-d O13 H5 M9E1266a-d O13 H6 M9 E1267a-d O13 H7 M9 E1268a-d O13 H8 M9 E1269a-d O13 H9M9 E1270a-d O14 H1 M9 E1271a-d O14 H2 M9 E1272a-d O14 H3 M9 E1273a-d O14H4 M9 E1274a-d O14 H5 M9 E1275a-d O14 H6 M9 E1276a-d O14 H7 M9 E1277a-dO14 H8 M9 E1278a-d O14 H9 M9 E1279a-d O15 H1 M9 E1280a-d O15 H2 M9E1281a-d O15 H3 M9 E1282a-d O15 H4 M9 E1283a-d O15 H5 M9 E1284a-d O15 H6M9 E1285a-d O15 H7 M9 E1286a-d O15 H8 M9 E1287a-d O15 H9 M9 E1288a-d O16H1 M9 E1289a-d O16 H2 M9 E1290a-d O16 H3 M9 E1291a-d O16 H4 M9 E1292a-dO16 H5 M9 E1293a-d O16 H6 M9 E1294a-d O16 H7 M9 E1295a-d O16 H8 M9E1296a-d O16 H9 M9 E1297a-d O1 H1 M10 E1298a-d O1 H2 M10 E1299a-d O1 H3M10 E1300a-d O1 H4 M10 E1301a-d O1 H5 M10 E1302a-d O1 H6 M10 E1303a-d O1H7 M10 E1304a-d O1 H8 M10 E1305a-d O1 H9 M10 E1306a-d O2 H1 M10 E1307a-dO2 H2 M10 E1308a-d O2 H3 M10 E1309a-d O2 H4 M10 E1310a-d O2 H5 M10E1311a-d O2 H6 M10 E1312a-d O2 H7 M10 E1313a-d O2 H8 M10 E1314a-d O2 H9M10 E1315a-d O3 H1 M10 E1316a-d O3 H2 M10 E1317a-d O3 H3 M10 E1318a-d O3H4 M10 E1319a-d O3 H5 M10 E1320a-d O3 H6 M10 E1321a-d O3 H7 M10 E1322a-dO3 H8 M10 E1323a-d O3 H9 M10 E1324a-d O4 H1 M10 E1325a-d O4 H2 M10E1326a-d O4 H3 M10 E1327a-d O4 H4 M10 E1328a-d O4 H5 M10 E1329a-d O4 H6M10 E1330a-d O4 H7 M10 E1331a-d O4 H8 M10 E1332a-d O4 H9 M10 E1333a-d O5H1 M10 E1334a-d O5 H2 M10 E1335a-d O5 H3 M10 E1336a-d O5 H4 M10 E1337a-dO5 H5 M10 E1338a-d O5 H6 M10 E1339a-d O5 H7 M10 E1340a-d O5 H8 M10E1341a-d O5 H9 M10 E1342a-d O6 H1 M10 E1343a-d O6 H2 M10 E1344a-d O6 H3M10 E1345a-d O6 H4 M10 E1346a-d O6 H5 M10 E1347a-d O6 H6 M10 E1348a-d O6H7 M10 E1349a-d O6 H8 M10 E1350a-d O6 H9 M10 E1351a-d O7 H1 M10 E1352a-dO7 H2 M10 E1353a-d O7 H3 M10 E1354a-d O7 H4 M10 E1355a-d O7 H5 M10E1356a-d O7 H6 M10 E1357a-d O7 H7 M10 E1358a-d O7 H8 M10 E1359a-d O7 H9M10 E1360a-d O8 H1 M10 E1361a-d O8 H2 M10 E1362a-d O8 H3 M10 E1363a-d O8H4 M10 E1364a-d O8 H5 M10 E1365a-d O8 H6 M10 E1366a-d O8 H7 M10 E1367a-dO8 H8 M10 E1368a-d O8 H9 M10 E1369a-d O9 H1 M10 E1370a-d O9 H2 M10E1371a-d O9 H3 M10 E1372a-d O9 H4 M10 E1373a-d O9 H5 M10 E1374a-d O9 H6M10 E1375a-d O9 H7 M10 E1376a-d O9 H8 M10 E1377a-d O9 H9 M10 E1378a-dO10 H1 M10 E1379a-d O10 H2 M10 E1380a-d O10 H3 M10 E1381a-d O10 H4 M10E1382a-d O10 H5 M10 E1383a-d O10 H6 M10 E1384a-d O10 H7 M10 E1385a-d O10H8 M10 E1386a-d O10 H9 M10 E1387a-d O11 H1 M10 E1388a-d O11 H2 M10E1389a-d O11 H3 M10 E1390a-d O11 H4 M10 E1391a-d O11 H5 M10 E1392a-d O11H6 M10 E1393a-d O11 H7 M10 E1394a-d O11 H8 M10 E1395a-d O11 H9 M10E1396a-d O12 H1 M10 E1397a-d O12 H2 M10 E1398a-d O12 H3 M10 E1399a-d O12H4 M10 E1400a-d O12 H5 M10 E1401a-d O12 H6 M10 E1402a-d O12 H7 M10E1403a-d O12 H8 M10 E1404a-d O12 H9 M10 E1405a-d O13 H1 M10 E1406a-d O13H2 M10 E1407a-d O13 H3 M10 E1408a-d O13 H4 M10 E1409a-d O13 H5 M10E1410a-d O13 H6 M10 E1411a-d O13 H7 M10 E1412a-d O13 H8 M10 E1413a-d O13H9 M10 E1414a-d O14 H1 M10 E1415a-d O14 H2 M10 E1416a-d O14 H3 M10E1417a-d O14 H4 M10 E1418a-d O14 H5 M10 E1419a-d O14 H6 M10 E1420a-d O14H7 M10 E1421a-d O14 H8 M10 E1422a-d O14 H9 M10 E1423a-d O15 H1 M10E1424a-d O15 H2 M10 E1425a-d O15 H3 M10 E1426a-d O15 H4 M10 E1427a-d O15H5 M10 E1428a-d O15 H6 M10 E1429a-d O15 H7 M10 E1430a-d O15 H8 M10E1431a-d O15 H9 M10 E1432a-d O16 H1 M10 E1433a-d O16 H2 M10 E1434a-d O16H3 M10 E1435a-d O16 H4 M10 E1436a-d O16 H5 M10 E1437a-d O16 H6 M10E1438a-d O16 H7 M10 E1439a-d O16 H8 M10 E1440a-d O16 H9 M10 E1441a-d O1H1 M11 E1442a-d O1 H2 M11 E1443a-d O1 H3 M11 E1444a-d O1 H4 M11 E1445a-dO1 H5 M11 E1446a-d O1 H6 M11 E1447a-d O1 H7 M11 E1448a-d O1 H8 M11E1449a-d O1 H9 M11 E1450a-d O2 H1 M11 E1451a-d O2 H2 M11 E1452a-d O2 H3M11 E1453a-d O2 H4 M11 E1454a-d O2 H5 M11 E1455a-d O2 H6 M11 E1456a-d O2H7 M11 E1457a-d O2 H8 M11 E1458a-d O2 H9 M11 E1459a-d O3 H1 M11 E1460a-dO3 H2 M11 E1461a-d O3 H3 M11 E1462a-d O3 H4 M11 E1463a-d O3 H5 M11E1464a-d O3 H6 M11 E1465a-d O3 H7 M11 E1466a-d O3 H8 M11 E1467a-d O3 H9M11 E1468a-d O4 H1 M11 E1469a-d O4 H2 M11 E1470a-d O4 H3 M11 E1471a-d O4H4 M11 E1472a-d O4 H5 M11 E1473a-d O4 H6 M11 E1474a-d O4 H7 M11 E1475a-dO4 H8 M11 E1476a-d O4 H9 M11 E1477a-d O5 H1 M11 E1478a-d O5 H2 M11E1479a-d O5 H3 M11 E1480a-d O5 H4 M11 E1481a-d O5 H5 M11 E1482a-d O5 H6M11 E1483a-d O5 H7 M11 E1484a-d O5 H8 M11 E1485a-d O5 H9 M11 E1486a-d O6H1 M11 E1487a-d O6 H2 M11 E1488a-d O6 H3 M11 E1489a-d O6 H4 M11 E1490a-dO6 H5 M11 E1491a-d O6 H6 M11 E1492a-d O6 H7 M11 E1493a-d O6 H8 M11E1494a-d O6 H9 M11 E1495a-d O7 H1 M11 E1496a-d O7 H2 M11 E1497a-d O7 H3M11 E1498a-d O7 H4 M11 E1499a-d O7 H5 M11 E1500a-d O7 H6 M11 E1501a-d O7H7 M11 E1502a-d O7 H8 M11 E1503a-d O7 H9 M11 E1504a-d O8 H1 M11 E1505a-dO8 H2 M11 E1506a-d O8 H3 M11 E1507a-d O8 H4 M11 E1508a-d O8 H5 M11E1509a-d O8 H6 M11 E1510a-d O8 H7 M11 E1511a-d O8 H8 M11 E1512a-d O8 H9M11 E1513a-d O9 H1 M11 E1514a-d O9 H2 M11 E1515a-d O9 H3 M11 E1516a-d O9H4 M11 E1517a-d O9 H5 M11 E1518a-d O9 H6 M11 E1519a-d O9 H7 M11 E1520a-dO9 H8 M11 E1521a-d O9 H9 M11 E1522a-d O10 H1 M11 E1523a-d O10 H2 M11E1524a-d O10 H3 M11 E1525a-d O10 H4 M11 E1526a-d O10 H5 M11 E1527a-d O10H6 M11 E1528a-d O10 H7 M11 E1529a-d O10 H8 M11 E1530a-d O10 H9 M11E1531a-d O11 H1 M11 E1532a-d O11 H2 M11 E1533a-d O11 H3 M11 E1534a-d O11H4 M11 E1535a-d O11 H5 M11 E1536a-d O11 H6 M11 E1537a-d O11 H7 M11E1538a-d O11 H8 M11 E1539a-d O11 H9 M11 E1540a-d O12 H1 M11 E1541a-d O12H2 M11 E1542a-d O12 H3 M11 E1543a-d O12 H4 M11 E1544a-d O12 H5 M11E1545a-d O12 H6 M11 E1546a-d O12 H7 M11 E1547a-d O12 H8 M11 E1548a-d O12H9 M11 E1549a-d O13 H1 M11 E1550a-d O13 H2 M11 E1551a-d O13 H3 M11E1552a-d O13 H4 M11 E1553a-d O13 H5 M11 E1554a-d O13 H6 M11 E1555a-d O13H7 M11 E1556a-d O13 H8 M11 E1557a-d O13 H9 M11 E1558a-d O14 H1 M11E1559a-d O14 H2 M11 E1560a-d O14 H3 M11 E1561a-d O14 H4 M11 E1562a-d O14H5 M11 E1563a-d O14 H6 M11 E1564a-d O14 H7 M11 E1565a-d O14 H8 M11E1566a-d O14 H9 M11 E1567a-d O15 H1 M11 E1568a-d O15 H2 M11 E1569a-d O15H3 M11 E1570a-d O15 H4 M11 E1571a-d O15 H5 M11 E1572a-d O15 H6 M11E1573a-d O15 H7 M11 E1574a-d O15 H8 M11 E1575a-d O15 H9 M11 E1576a-d O16H1 M11 E1577a-d O16 H2 M11 E1578a-d O16 H3 M11 E1579a-d O16 H4 M11E1580a-d O16 H5 M11 E1581a-d O16 H6 M11 E1582a-d O16 H7 M11 E1583a-d O16H8 M11 E1584a-d O16 H9 M11 E1585a-d O1 H1 M12 E1586a-d O1 H2 M12E1587a-d O1 H3 M12 E1588a-d O1 H4 M12 E1589a-d O1 H5 M12 E1590a-d O1 H6M12 E1591a-d O1 H7 M12 E1592a-d O1 H8 M12 E1593a-d O1 H9 M12 E1594a-d O2H1 M12 E1595a-d O2 H2 M12 E1596a-d O2 H3 M12 E1597a-d O2 H4 M12 E1598a-dO2 H5 M12 E1599a-d O2 H6 M12 E1600a-d O2 H7 M12 E1601a-d O2 H8 M12E1602a-d O2 H9 M12 E1603a-d O3 H1 M12 E1604a-d O3 H2 M12 E1605a-d O3 H3M12 E1606a-d O3 H4 M12 E1607a-d O3 H5 M12 E1608a-d O3 H6 M12 E1609a-d O3H7 M12 E1610a-d O3 H8 M12 E1611a-d O3 H9 M12 E1612a-d O4 H1 M12 E1613a-dO4 H2 M12 E1614a-d O4 H3 M12 E1615a-d O4 H4 M12 E1616a-d O4 H5 M12E1617a-d O4 H6 M12 E1618a-d O4 H7 M12 E1619a-d O4 H8 M12 E1620a-d O4 H9M12 E1621a-d O5 H1 M12 E1622a-d O5 H2 M12 E1623a-d O5 H3 M12 E1624a-d O5H4 M12 E1625a-d O5 H5 M12 E1626a-d O5 H6 M12 E1627a-d O5 H7 M12 E1628a-dO5 H8 M12 E1629a-d O5 H9 M12 E1630a-d O6 H1 M12 E1631a-d O6 H2 M12E1632a-d O6 H3 M12 E1633a-d O6 H4 M12 E1634a-d O6 H5 M12 E1635a-d O6 H6M12 E1636a-d O6 H7 M12 E1637a-d O6 H8 M12 E1638a-d O6 H9 M12 E1639a-d O7H1 M12 E1640a-d O7 H2 M12 E1641a-d O7 H3 M12 E1642a-d O7 H4 M12 E1643a-dO7 H5 M12 E1644a-d O7 H6 M12 E1645a-d O7 H7 M12 E1646a-d O7 H8 M12E1647a-d O7 H9 M12 E1648a-d O8 H1 M12 E1649a-d O8 H2 M12 E1650a-d O8 H3M12 E1651a-d O8 H4 M12 E1652a-d O8 H5 M12 E1653a-d O8 H6 M12 E1654a-d O8H7 M12 E1655a-d O8 H8 M12 E1656a-d O8 H9 M12 E1657a-d O9 H1 M12 E1658a-dO9 H2 M12 E1659a-d O9 H3 M12 E1660a-d O9 H4 M12 E1661a-d O9 H5 M12E1662a-d O9 H6 M12 E1663a-d O9 H7 M12 E1664a-d O9 H8 M12 E1665a-d O9 H9M12 E1666a-d O10 H1 M12 E1667a-d O10 H2 M12 E1668a-d O10 H3 M12 E1669a-dO10 H4 M12 E1670a-d O10 H5 M12 E1671a-d O10 H6 M12 E1672a-d O10 H7 M12E1673a-d O10 H8 M12 E1674a-d O10 H9 M12 E1675a-d O11 H1 M12 E1676a-d O11H2 M12 E1677a-d O11 H3 M12 E1678a-d O11 H4 M12 E1679a-d O11 H5 M12E1680a-d O11 H6 M12 E1681a-d O11 H7 M12 E1682a-d O11 H8 M12 E1683a-d O11H9 M12 E1684a-d O12 H1 M12 E1685a-d O12 H2 M12 E1686a-d O12 H3 M12E1687a-d O12 H4 M12 E1688a-d O12 H5 M12 E1689a-d O12 H6 M12 E1690a-d O12H7 M12 E1691a-d O12 H8 M12 E1692a-d O12 H9 M12 E1693a-d O13 H1 M12E1694a-d O13 H2 M12 E1695a-d O13 H3 M12 E1696a-d O13 H4 M12 E1697a-d O13H5 M12 E1698a-d O13 H6 M12 E1699a-d O13 H7 M12 E1700a-d O13 H8 M12E1701a-d O13 H9 M12 E1702a-d O14 H1 M12 E1703a-d O14 H2 M12 E1704a-d O14H3 M12 E1705a-d O14 H4 M12 E1706a-d O14 H5 M12 E1707a-d O14 H6 M12E1708a-d O14 H7 M12 E1709a-d O14 H8 M12 E1710a-d O14 H9 M12 E1711a-d O15H1 M12 E1712a-d O15 H2 M12 E1713a-d O15 H3 M12 E1714a-d O15 H4 M12E1715a-d O15 H5 M12 E1716a-d O15 H6 M12 E1717a-d O15 H7 M12 E1718a-d O15H8 M12 E1719a-d O15 H9 M12 E1720a-d O16 H1 M12 E1721a-d O16 H2 M12E1722a-d O16 H3 M12 E1723a-d O16 H4 M12 E1724a-d O16 H5 M12 E1725a-d O16H6 M12 E1726a-d O16 H7 M12 E1727a-d O16 H8 M12 E1728a-d O16 H9 M12E1729a-d O1 H1 M13 E1730a-d O1 H2 M13 E1731a-d O1 H3 M13 E1732a-d O1 H4M13 E1733a-d O1 H5 M13 E1734a-d O1 H6 M13 E1735a-d O1 H7 M13 E1736a-d O1H8 M13 E1737a-d O1 H9 M13 E1738a-d O2 H1 M13 E1739a-d O2 H2 M13 E1740a-dO2 H3 M13 E1741a-d O2 H4 M13 E1742a-d O2 H5 M13 E1743a-d O2 H6 M13E1744a-d O2 H7 M13 E1745a-d O2 H8 M13 E1746a-d O2 H9 M13 E1747a-d O3 H1M13 E1748a-d O3 H2 M13 E1749a-d O3 H3 M13 E1750a-d O3 H4 M13 E1751a-d O3H5 M13 E1752a-d O3 H6 M13 E1753a-d O3 H7 M13 E1754a-d O3 H8 M13 E1755a-dO3 H9 M13 E1756a-d O4 H1 M13 E1757a-d O4 H2 M13 E1758a-d O4 H3 M13E1759a-d O4 H4 M13 E1760a-d O4 H5 M13 E1761a-d O4 H6 M13 E1762a-d O4 H7M13 E1763a-d O4 H8 M13 E1764a-d O4 H9 M13 E1765a-d O5 H1 M13 E1766a-d O5H2 M13 E1767a-d O5 H3 M13 E1768a-d O5 H4 M13 E1769a-d O5 H5 M13 E1770a-dO5 H6 M13 E1771a-d O5 H7 M13 E1772a-d O5 H8 M13 E1773a-d O5 H9 M13E1774a-d O6 H1 M13 E1775a-d O6 H2 M13 E1776a-d O6 H3 M13 E1777a-d O6 H4M13 E1778a-d O6 H5 M13 E1779a-d O6 H6 M13 E1780a-d O6 H7 M13 E1781a-d O6H8 M13 E1782a-d O6 H9 M13 E1783a-d O7 H1 M13 E1784a-d O7 H2 M13 E1785a-dO7 H3 M13 E1786a-d O7 H4 M13 E1787a-d O7 H5 M13 E1788a-d O7 H6 M13E1789a-d O7 H7 M13 E1790a-d O7 H8 M13 E1791a-d O7 H9 M13 E1792a-d O8 H1M13 E1793a-d O8 H2 M13 E1794a-d O8 H3 M13 E1795a-d O8 H4 M13 E1796a-d O8H5 M13 E1797a-d O8 H6 M13 E1798a-d O8 H7 M13 E1799a-d O8 H8 M13 E1800a-dO8 H9 M13 E1801a-d O9 H1 M13 E1802a-d O9 H2 M13 E1803a-d O9 H3 M13E1804a-d O9 H4 M13 E1805a-d O9 H5 M13 E1806a-d O9 H6 M13 E1807a-d O9 H7M13 E1808a-d O9 H8 M13 E1809a-d O9 H9 M13 E1810a-d O10 H1 M13 E1811a-dO10 H2 M13 E1812a-d O10 H3 M13 E1813a-d O10 H4 M13 E1814a-d O10 H5 M13E1815a-d O10 H6 M13 E1816a-d O10 H7 M13 E1817a-d O10 H8 M13 E1818a-d O10H9 M13 E1819a-d O11 H1 M13 E1820a-d O11 H2 M13 E1821a-d O11 H3 M13E1822a-d O11 H4 M13 E1823a-d O11 H5 M13 E1824a-d O11 H6 M13 E1825a-d O11H7 M13 E1826a-d O11 H8 M13 E1827a-d O11 H9 M13 E1828a-d O12 H1 M13E1829a-d O12 H2 M13 E1830a-d O12 H3 M13 E1831a-d O12 H4 M13 E1832a-d O12H5 M13 E1833a-d O12 H6 M13 E1834a-d O12 H7 M13 E1835a-d O12 H8 M13E1836a-d O12 H9 M13 E1837a-d O13 H1 M13 E1838a-d O13 H2 M13 E1839a-d O13H3 M13 E1840a-d O13 H4 M13 E1841a-d O13 H5 M13 E1842a-d O13 H6 M13E1843a-d O13 H7 M13 E1844a-d O13 H8 M13 E1845a-d O13 H9 M13 E1846a-d O14H1 M13 E1847a-d O14 H2 M13 E1848a-d O14 H3 M13 E1849a-d O14 H4 M13E1850a-d O14 H5 M13 E1851a-d O14 H6 M13 E1852a-d O14 H7 M13 M13 E1853a-dO14 H8 M13 E1854a-d O14 H9 M13 E1855a-d O15 H1 M13 E1856a-d O15 H2 M13E1857a-d O15 H3 M13 E1858a-d O15 H4 M13 E1859a-d O15 H5 M13 E1860a-d O15H6 M13 E1861a-d O15 H7 M13 E1862a-d O15 H8 M13 E1863a-d O15 H9 M13E1864a-d O16 H1 M13 E1865a-d O16 H2 M13 E1866a-d O16 H3 M13 E1867a-d O16H4 M13 E1868a-d O16 H5 M13 E1869a-d O16 H6 M13 E1870a-d O16 H7 M13E1871a-d O16 H8 M13 E1872a-d O16 H9 M13 E1873a-d O1 H1 M14 E1874a-d O1H2 M14 E1875a-d O1 H3 M14 E1876a-d O1 H4 M14 E1877a-d O1 H5 M14 E1878a-dO1 H6 M14 E1879a-d O1 H7 M14 E1880a-d O1 H8 M14 E1881a-d O1 H9 M14E1882a-d O2 H1 M14 E1883a-d O2 H2 M14 E1884a-d O2 H3 M14 E1885a-d O2 H4M14 E1886a-d O2 H5 M14 E1887a-d O2 H6 M14 E1888a-d O2 H7 M14 E1889a-d O2H8 M14 E1890a-d O2 H9 M14 E1891a-d O3 H1 M14 E1892a-d O3 H2 M14 E1893a-dO3 H3 M14 E1894a-d O3 H4 M14 E1895a-d O3 H5 M14 E1896a-d O3 H6 M14E1897a-d O3 H7 M14 E1898a-d O3 H8 M14 E1899a-d O3 H9 M14 E1900a-d O4 H1M14 E1901a-d O4 H2 M14 E1902a-d O4 H3 M14 E1903a-d O4 H4 M14 E1904a-d O4H5 M14 E1905a-d O4 H6 M14 E1906a-d O4 H7 M14 E1907a-d O4 H8 M14 E1908a-dO4 H9 M14 E1909a-d O5 H1 M14 E1910a-d O5 H2 M14 E1911a-d O5 H3 M14E1912a-d O5 H4 M14 E1913a-d O5 H5 M14 E1914a-d O5 H6 M14 E1915a-d O5 H7M14 E1916a-d O5 H8 M14 E1917a-d O5 H9 M14 E1918a-d O6 H1 M14 E1919a-d O6H2 M14 E1920a-d O6 H3 M14 E1921a-d O6 H4 M14 E1922a-d O6 H5 M14 E1923a-dO6 H6 M14 E1924a-d O6 H7 M14 E1925a-d O6 H8 M14 E1926a-d O6 H9 M14E1927a-d O7 H1 M14 E1928a-d O7 H2 M14 E1929a-d O7 H3 M14 E1930a-d O7 H4M14 E1931a-d O7 H5 M14 E1932a-d O7 H6 M14 E1933a-d O7 H7 M14 E1934a-d O7H8 M14 E1935a-d O7 H9 M14 E1936a-d O8 H1 M14 E1937a-d O8 H2 M14 E1938a-dO8 H3 M14 E1939a-d O8 H4 M14 E1940a-d O8 H5 M14 E1941a-d O8 H6 M14E1942a-d O8 H7 M14 E1943a-d O8 H8 M14 E1944a-d O8 H9 M14 E1945a-d O9 H1M14 E1946a-d O9 H2 M14 E1947a-d O9 H3 M14 E1948a-d O9 H4 M14 E1949a-d O9H5 M14 E1950a-d O9 H6 M14 E1951a-d O9 H7 M14 E1952a-d O9 H8 M14 E1953a-dO9 H9 M14 E1954a-d O10 H1 M14 E1955a-d O10 H2 M14 E1956a-d O10 H3 M14E1957a-d O10 H4 M14 E1958a-d O10 H5 M14 E1959a-d O10 H6 M14 E1960a-d O10H7 M14 E1961a-d O10 H8 M14 E1962a-d O10 H9 M14 E1963a-d O11 H1 M14E1964a-d O11 H2 M14 E1965a-d O11 H3 M14 E1966a-d O11 H4 M14 E1967a-d O11H5 M14 E1968a-d O11 H6 M14 E1969a-d O11 H7 M14 E1970a-d O11 H8 M14E1971a-d O11 H9 M14 E1972a-d O12 H1 M14 E1973a-d O12 H2 M14 E1974a-d O12H3 M14 E1975a-d O12 H4 M14 E1976a-d O12 H5 M14 E1977a-d O12 H6 M14E1978a-d O12 H7 M14 E1979a-d O12 H8 M14 E1980a-d O12 H9 M14 E1981a-d O13H1 M14 E1982a-d O13 H2 M14 E1983a-d O13 H3 M14 E1984a-d O13 H4 M14E1985a-d O13 H5 M14 E1986a-d O13 H6 M14 E1987a-d O13 H7 M14 E1988a-d O13H8 M14 E1989a-d O13 H9 M14 E1990a-d O14 H1 M14 E1991a-d O14 H2 M14E1992a-d O14 H3 M14 E1993a-d O14 H4 M14 E1994a-d O14 H5 M14 E1995a-d O14H6 M14 E1996a-d O14 H7 M14 E1997a-d O14 H8 M14 E1998a-d O14 H9 M14E1999a-d O15 H1 M14 E2000a-d O15 H2 M14 E2001a-d O15 H3 M14 E2002a-d O15H4 M14 E2003a-d O15 H5 M14 E2004a-d O15 H6 M14 E2005a-d O15 H7 M14E2006a-d O15 H8 M14 E2007a-d O15 H9 M14 E2008a-d O16 H1 M14 E2009a-d O16H2 M14 E2010a-d O16 H3 M14 E2011a-d O16 H4 M14 E2012a-d O16 H5 M14E2013a-d O16 H6 M14 E2014a-d O16 H7 M14 E2015a-d O16 H8 M14 E2016a-d O16H9 M14 E2017a-d O1 H1 M15 E2018a-d O1 H2 M15 E2019a-d O1 H3 M15 E2020a-dO1 H4 M15 E2021a-d O1 H5 M15 E2022a-d O1 H6 M15 E2023a-d O1 H7 M15E2024a-d O1 H8 M15 E2025a-d O1 H9 M15 E2026a-d O2 H1 M15 E2027a-d O2 H2M15 E2028a-d O2 H3 M15 E2029a-d O2 H4 M15 E2030a-d O2 H5 M15 E2031a-d O2H6 M15 E2032a-d O2 H7 M15 E2033a-d O2 H8 M15 E2034a-d O2 H9 M15 E2035a-dO3 H1 M15 E2036a-d O3 H2 M15 E2037a-d O3 H3 M15 E2038a-d O3 H4 M15E2039a-d O3 H5 M15 E2040a-d O3 H6 M15 E2041a-d O3 H7 M15 E2042a-d O3 H8M15 E2043a-d O3 H9 M15 E2044a-d O4 H1 M15 E2045a-d O4 H2 M15 E2046a-d O4H3 M15 E2047a-d O4 H4 M15 E2048a-d O4 H5 M15 E2049a-d O4 H6 M15 E2050a-dO4 H7 M15 E2051a-d O4 H8 M15 E2052a-d O4 H9 M15 E2053a-d O5 H1 M15E2054a-d O5 H2 M15 E2055a-d O5 H3 M15 E2056a-d O5 H4 M15 E2057a-d O5 H5M15 E2058a-d O5 H6 M15 E2059a-d O5 H7 M15 E2060a-d O5 H8 M15 E2061a-d O5H9 M15 E2062a-d O6 H1 M15 E2063a-d O6 H2 M15 E2064a-d O6 H3 M15 E2065a-dO6 H4 M15 E2066a-d O6 H5 M15 E2067a-d O6 H6 M15 E2068a-d O6 H7 M15E2069a-d O6 H8 M15 E2070a-d O6 H9 M15 E2071a-d O7 H1 M15 E2072a-d O7 H2M15 E2073a-d O7 H3 M15 E2074a-d O7 H4 M15 E2075a-d O7 H5 M15 E2076a-d O7H6 M15 E2077a-d O7 H7 M15 E2078a-d O7 H8 M15 E2079a-d O7 H9 M15 E2080a-dO8 H1 M15 E2081a-d O8 H2 M15 E2082a-d O8 H3 M15 E2083a-d O8 H4 M15E2084a-d O8 H5 M15 E2085a-d O8 H6 M15 E2086a-d O8 H7 M15 E2087a-d O8 H8M15 E2088a-d O8 H9 M15 E2089a-d O9 H1 M15 E2090a-d O9 H2 M15 E2091a-d O9H3 M15 E2092a-d O9 H4 M15 E2093a-d O9 H5 M15 E2094a-d O9 H6 M15 E2095a-dO9 H7 M15 E2096a-d O9 H8 M15 E2097a-d O9 H9 M15 E2098a-d O10 H1 M15E2099a-d O10 H2 M15 E2100a-d O10 H3 M15 E2101a-d O10 H4 M15 E2102a-d O10H5 M15 E2103a-d O10 H6 M15 E2104a-d O10 H7 M15 E2105a-d O10 H8 M15E2106a-d O10 H9 M15 E2107a-d O11 H1 M15 E2108a-d O11 H2 M15 E2109a-d O11H3 M15 E2110a-d O11 H4 M15 E2111a-d O11 H5 M15 E2112a-d O11 H6 M15E2113a-d O11 H7 M15 E2114a-d O11 H8 M15 E2115a-d O11 H9 M15 E2116a-d O12H1 M15 E2117a-d O12 H2 M15 E2118a-d O12 H3 M15 E2119a-d O12 H4 M15E2120a-d O12 H5 M15 E2121a-d O12 H6 M15 E2122a-d O12 H7 M15 E2123a-d O12H8 M15 E2124a-d O12 H9 M15 E2125a-d O13 H1 M15 E2126a-d O13 H2 M15E2127a-d O13 H3 M15 E2128a-d O13 H4 M15 E2129a-d O13 H5 M15 E2130a-d O13H6 M15 E2131a-d O13 H7 M15 E2132a-d O13 H8 M15 E2133a-d O13 H9 M15E2134a-d O14 H1 M15 E2135a-d O14 H2 M15 E2136a-d O14 H3 M15 E2137a-d O14H4 M15 E2138a-d O14 H5 M15 E2139a-d O14 H6 M15 E2140a-d O14 H7 M15E2141a-d O14 H8 M15 E2142a-d O14 H9 M15 E2143a-d O15 H1 M15 E2144a-d O15H2 M15 E2145a-d O15 H3 M15 E2146a-d O15 H4 M15 E2147a-d O15 H5 M15E2148a-d O15 H6 M15 E2149a-d O15 H7 M15 E2150a-d O15 H8 M15 E2151a-d O15H9 M15 E2152a-d O16 H1 M15 E2153a-d O16 H2 M15 E2154a-d O16 H3 M15E2155a-d O16 H4 M15 E2156a-d O16 H5 M15 E2157a-d O16 H6 M15 E2158a-d O16H7 M15 E2159a-d O16 H8 M15 E2160a-d O16 H9 M15 E2161a-d O1 H1 M16E2162a-d O1 H2 M16 E2163a-d O1 H3 M16 E2164a-d O1 H4 M16 E2165a-d O1 H5M16 E2166a-d O1 H6 M16 E2167a-d O1 H7 M16 E2168a-d O1 H8 M16 E2169a-d O1H9 M16 E2170a-d O2 H1 M16 E2171a-d O2 H2 M16 E2172a-d O2 H3 M16 E2173a-dO2 H4 M16 E2174a-d O2 H5 M16 E2175a-d O2 H6 M16 E2176a-d O2 H7 M16E2177a-d O2 H8 M16 E2178a-d O2 H9 M16 E2179a-d O3 H1 M16 E2180a-d O3 H2M16 E2181a-d O3 H3 M16 E2182a-d O3 H4 M16 E2183a-d O3 H5 M16 E2184a-d O3H6 M16 E2185a-d O3 H7 M16 E2186a-d O3 H8 M16 E2187a-d O3 H9 M16 E2188a-dO4 H1 M16 E2189a-d O4 H2 M16 E2190a-d O4 H3 M16 E2191a-d O4 H4 M16E2192a-d O4 H5 M16 E2193a-d O4 H6 M16 E2194a-d O4 H7 M16 E2195a-d O4 H8M16 E2196a-d O4 H9 M16 E2197a-d O5 H1 M16 E2198a-d O5 H2 M16 E2199a-d O5H3 M16 E2200a-d O5 H4 M16 E2201a-d O5 H5 M16 E2202a-d O5 H6 M16 E2203a-dO5 H7 M16 E2204a-d O5 H8 M16 E2205a-d O5 H9 M16 E2206a-d O6 H1 M16E2207a-d O6 H2 M16 E2208a-d O6 H3 M16 E2209a-d O6 H4 M16 E2210a-d O6 H5M16 E2211a-d O6 H6 M16 E2212a-d O6 H7 M16 E2213a-d O6 H8 M16 E2214a-d O6H9 M16 E2215a-d O7 H1 M16 E2216a-d O7 H2 M16 E2217a-d O7 H3 M16 E2218a-dO7 H4 M16 E2219a-d O7 H5 M16 E2220a-d O7 H6 M16 E2221a-d O7 H7 M16E2222a-d O7 H8 M16 E2223a-d O7 H9 M16 E2224a-d O8 H1 M16 E2225a-d O8 H2M16 E2226a-d O8 H3 M16 E2227a-d O8 H4 M16 E2228a-d O8 H5 M16 E2229a-d O8H6 M16 E2230a-d O8 H7 M16 E2231a-d O8 H8 M16 E2232a-d O8 H9 M16 E2233a-dO9 H1 M16 E2234a-d O9 H2 M16 E2235a-d O9 H3 M16 E2236a-d O9 H4 M16E2237a-d O9 H5 M16 E2238a-d O9 H6 M16 E2239a-d O9 H7 M16 E2240a-d O9 H8M16 E2241a-d O9 H9 M16 E2242a-d O10 H1 M16 E2243a-d O10 H2 M16 E2244a-dO10 H3 M16 E2245a-d O10 H4 M16 E2246a-d O10 H5 M16 E2247a-d O10 H6 M16E2248a-d O10 H7 M16 E2249a-d O10 H8 M16 E2250a-d O10 H9 M16 E2251a-d O11H1 M16 E2252a-d O11 H2 M16 E2253a-d O11 H3 M16 E2254a-d O11 H4 M16E2255a-d O11 H5 M16 E2256a-d O11 H6 M16 E2257a-d O11 H7 M16 E2258a-d O11H8 M16 E2259a-d O11 H9 M16 E2260a-d O12 H1 M16 E2261a-d O12 H2 M16E2262a-d O12 H3 M16 E2263a-d O12 H4 M16 E2264a-d O12 H5 M16 E2265a-d O12H6 M16 E2266a-d O12 H7 M16 E2267a-d O12 H8 M16 E2268a-d O12 H9 M16E2269a-d O13 H1 M16 E2270a-d O13 H2 M16 E2271a-d O13 H3 M16 E2272a-d O13H4 M16 E2273a-d O13 H5 M16 E2274a-d O13 H6 M16 E2275a-d O13 H7 M16E2276a-d O13 H8 M16 E2277a-d O13 H9 M16 E2278a-d O14 H1 M16 E2279a-d O14H2 M16 E2280a-d O14 H3 M16 E2281a-d O14 H4 M16 E2282a-d O14 H5 M16E2283a-d O14 H6 M16 E2284a-d O14 H7 M16 E2285a-d O14 H8 M16 E2286a-d O14H9 M16 E2287a-d O15 H1 M16 E2288a-d O15 H2 M16 E2289a-d O15 H3 M16E2290a-d O15 H4 M16 E2291a-d O15 H5 M16 E2292a-d O15 H6 M16 E2293a-d O15H7 M16 E2294a-d O15 H8 M16 E2295a-d O15 H9 M16 E2296a-d O16 H1 M16E2297a-d O16 H2 M16 E2298a-d O16 H3 M16 E2299a-d O16 H4 M16 E2300a-d O16H5 M16 E2301a-d O16 H6 M16 E2302a-d O16 H7 M16 E2303a-d O16 H8 M16E2304a-d O16 H9 M16 E2305a-d O1 H1 M17 E2306a-d O1 H2 M17 E2307a-d O1 H3M17 E2308a-d O1 H4 M17 E2309a-d O1 H5 M17 E2310a-d O1 H6 M17 E2311a-d O1H7 M17 E2312a-d O1 H8 M17 E2313a-d O1 H9 M17 E2314a-d O2 H1 M17 E2315a-dO2 H2 M17 E2316a-d O2 H3 M17 E2317a-d O2 H4 M17 E2318a-d O2 H5 M17E2319a-d O2 H6 M17 E2320a-d O2 H7 M17 E2321a-d O2 H8 M17 E2322a-d O2 H9M17 E2323a-d O3 H1 M17 E2324a-d O3 H2 M17 E2325a-d O3 H3 M17 E2326a-d O3H4 M17 E2327a-d O3 H5 M17 E2328a-d O3 H6 M17 E2329a-d O3 H7 M17 E2330a-dO3 H8 M17 E2331a-d O3 H9 M17 E2332a-d O4 H1 M17 E2333a-d O4 H2 M17E2334a-d O4 H3 M17 E2335a-d O4 H4 M17 E2336a-d O4 H5 M17 E2337a-d O4 H6M17 E2338a-d O4 H7 M17 E2339a-d O4 H8 M17 E2340a-d O4 H9 M17 E2341a-d O5H1 M17 E2342a-d O5 H2 M17 E2343a-d O5 H3 M17 E2344a-d O5 H4 M17 E2345a-dO5 H5 M17 E2346a-d O5 H6 M17 E2347a-d O5 H7 M17 E2348a-d O5 H8 M17E2349a-d O5 H9 M17 E2350a-d O6 H1 M17 E2351a-d O6 H2 M17 E2352a-d O6 H3M17 E2353a-d O6 H4 M17 E2354a-d O6 H5 M17 E2355a-d O6 H6 M17 E2356a-d O6H7 M17 E2357a-d O6 H8 M17 E2358a-d O6 H9 M17 E2359a-d O7 H1 M17 E2360a-dO7 H2 M17 E2361a-d O7 H3 M17 E2362a-d O7 H4 M17 E2363a-d O7 H5 M17E2364a-d O7 H6 M17 E2365a-d O7 H7 M17 E2366a-d O7 H8 M17 E2367a-d O7 H9M17 E2368a-d O8 H1 M17 E2369a-d O8 H2 M17 EZ370a-d O8 H3 M17 E2371a-d O8H4 M17 E2372a-d O8 H5 M17 E2373a-d O8 H6 M17 E2374a-d O8 H7 M17 E2375a-dO8 H8 M17 E2376a-d O8 H9 M17 E2377a-d O9 H1 M17 E2378a-d O9 H2 M17E2379a-d O9 H3 M17 E2380a-d O9 H4 M17 E2381a-d O9 H5 M17 E2382a-d O9 H6M17 E2383a-d O9 H7 M17 E2384a-d O9 H8 M17 E2385a-d O9 H9 M17 E2386a-dO10 H1 M17 E2387a-d O10 H2 M17 E2388a-d O10 H3 M17 E2389a-d O10 H4 M17E2390a-d O10 H5 M17 E2391a-d O10 H6 M17 E2392a-d O10 H7 M17 E2393a-d O10H8 M17 E2394a-d O10 H9 M17 E2395a-d O11 H1 M17 E2396a-d O11 H2 M17E2397a-d O11 H3 M17 E2398a-d O11 H4 M17 E2399a-d O11 H5 M17 E2400a-d O11H6 M17 E2401a-d O11 H7 M17 E2402a-d O11 H8 M17 E2403a-d O11 H9 M17E2404a-d O12 H1 M17 E2405a-d O12 H2 M17 E2406a-d O12 H3 M17 E2407a-d O12H4 M17 E2408a-d O12 H5 M17 E2409a-d O12 H6 M17 E2410a-d O12 H7 M17E2411a-d O12 H8 M17 E2412a-d O12 H9 M17 E2413a-d O13 H1 M17 E2414a-d O13H2 M17 E2415a-d O13 H3 M17 E2416a-d O13 H4 M17 E2417a-d O13 H5 M17E2418a-d O13 H6 M17 E2419a-d O13 H7 M17 E2420a-d O13 H8 M17 E2421a-d O13H9 M17 E2422a-d O14 H1 M17 E2423a-d O14 H2 M17 E2424a-d O14 H3 M17E2425a-d O14 H4 M17 E2426a-d O14 H5 M17 E2427a-d O14 H6 M17 E2428a-d O14H7 M17 E2429a-d O14 H8 M17 E2430a-d O14 H9 M17 E2431a-d O15 H1 M17E2432a-d O15 H2 M17 E2433a-d O15 H3 M17 E2434a-d O15 H4 M17 E2435a-d O15H5 M17 E2436a-d O15 H6 M17 E2437a-d O15 H7 M17 E2438a-d O15 H8 M17E2439a-d O15 H9 M17 E2440a-d O16 H1 M17 E2441a-d O16 H2 M17 E2442a-d O16H3 M17 E2443a-d O16 H4 M17 E2444a-d O16 H5 M17 E2445a-d O16 H6 M17E2446a-d O16 H7 M17 E2447a-d O16 H8 M17 E2448a-d O16 H9 M17 E2449a-d O1H1 M18 E2450a-d O1 H2 M18 E2451a-d O1 H3 M18 E2452a-d O1 H4 M18 E2453a-dO1 H5 M18 E2454a-d O1 H6 M18 E2455a-d O1 H7 M18 E2456a-d O1 H8 M18E2457a-d O1 H9 M18 E2458a-d O2 H1 M18 E2459a-d O2 H2 M18 E2460a-d O2 H3M18 E2461a-d O2 H4 M18 E2462a-d O2 H5 M18 E2463a-d O2 H6 M18 E2464a-d O2H7 M18 E2465a-d O2 H8 M18 E2466a-d O2 H9 M18 E2467a-d O3 H1 M18 E2468a-dO3 H2 M18 E2469a-d O3 H3 M18 E2470a-d O3 H4 M18 E2471a-d O3 H5 M18E2472a-d O3 H6 M18 E2473a-d O3 H7 M18 E2474a-d O3 H8 M18 E2475a-d O3 H9M18 E2476a-d O4 H1 M18 E2477a-d O4 H2 M18 E2478a-d O4 H3 M18 E2479a-d O4H4 M18 E2480a-d O4 H5 M18 E2481a-d O4 H6 M18 E2482a-d O4 H7 M18 E2483a-dO4 H8 M18 E2484a-d O4 H9 M18 E2485a-d O5 H1 M18 E2486a-d O5 H2 M18E2487a-d O5 H3 M18 E2488a-d O5 H4 M18 E2489a-d O5 H5 M18 E2490a-d O5 H6M18 E2491a-d O5 H7 M18 E2492a-d O5 H8 M18 E2493a-d O5 H9 M18 E2494a-d O6H1 M18 E2495a-d O6 H2 M18 E2496a-d O6 H3 M18 E2497a-d O6 H4 M18 E2498a-dO6 H5 M18 E2499a-d O6 H6 M18 E2500a-d O6 H7 M18 E2501a-d O6 H8 M18E2502a-d O6 H9 M18 E2503a-d O7 H1 M18 E2504a-d O7 H2 M18 E2505a-d O7 H3M18 E2506a-d O7 H4 M18 E2507a-d O7 H5 M18 E2508a-d O7 H6 M18 E2509a-d O7H7 M18 E2510a-d O7 H8 M18 E2511a-d O7 H9 M18 E2512a-d O8 H1 M18 E2513a-dO8 H2 M18 E2514a-d O8 H3 M18 E2515a-d O8 H4 M18 E2516a-d O8 H5 M18E2517a-d O8 H6 M18 E2518a-d O8 H7 M18 E2519a-d O8 H8 M18 E2520a-d O8 H9M18 E2521a-d O9 H1 M18 E2522a-d O9 H2 M18 E2523a-d O9 H3 M18 E2524a-d O9H4 M18 E2525a-d O9 H5 M18 E2526a-d O9 H6 M18 E2527a-d O9 H7 M18 E2528a-dO9 H8 M18 E2529a-d O9 H9 M18 E2530a-d O10 H1 M18 E2531a-d O10 H2 M18E2532a-d O10 H3 M18 E2533a-d O10 H4 M18 E2534a-d O10 H5 M18 E2535a-d O10H6 M18 E2536a-d O10 H7 M18 E2537a-d O10 H8 M18 E2538a-d O10 H9 M18E2539a-d O11 H1 M18 E2540a-d O11 H2 M18 E2541a-d O11 H3 M18 E2542a-d O11H4 M18 E2543a-d O11 H5 M18 E2544a-d O11 H6 M18 E2545a-d O11 H7 M18E2546a-d O11 H8 M18 E2547a-d O11 H9 M18 E2548a-d O12 H1 M18 E2549a-d O12H2 M18 E2550a-d O12 H3 M18 E2551a-d O12 H4 M18 E2552a-d O12 H5 M18E2553a-d O12 H6 M18 E2554a-d O12 H7 M18 E2555a-d O12 H8 M18 E2556a-d O12H9 M18 E2557a-d O13 H1 M18 E2558a-d O13 H2 M18 E2559a-d O13 H3 M18E2560a-d O13 H4 M18 E2561a-d O13 H5 M18 E2562a-d O13 H6 M18 E2563a-d O13H7 M18 E2564a-d O13 H8 M18 E2565a-d O13 H9 M18 E2566a-d O14 H1 M18E2567a-d O14 H2 M18 E2568a-d O14 H3 M18 E2569a-d O14 H4 M18 E2570a-d O14H5 M18 E2571a-d O14 H6 M18 E2572a-d O14 H7 M18 E2573a-d O14 H8 M18E2574a-d O14 H9 M18 E2575a-d O15 H1 M18 E2576a-d O15 H2 M18 E2577a-d O15H3 M18 E2578a-d O15 H4 M18 E2579a-d O15 H5 M18 E2580a-d O15 H6 M18E2581a-d O15 H7 M18 E2582a-d O15 H8 M18 E2583a-d O15 H9 M18 E2584a-d O16H1 M18 E2585a-d O16 H2 M18 E2586a-d O16 H3 M18 E2587a-d O16 H4 M18E2588a-d O16 H5 M18 E2589a-d O16 H6 M18 E2590a-d O16 H7 M18 E2591a-d O16H8 M18 E2592a-d O16 H9 M18 E2593a-d O1 H1 M19 E2594a-d O1 H2 M19E2595a-d O1 H3 M19 E2596a-d O1 H4 M19 E2597a-d O1 H5 M19 E2598a-d O1 H6M19 E2599a-d O1 H7 M19 E2600a-d O1 H8 M19 E2601a-d O1 H9 M19 E2602a-d O2H1 M19 E2603a-d O2 H2 M19 E2604a-d O2 H3 M19 E2605a-d O2 H4 M19 E2606a-dO2 H5 M19 E2607a-d O2 H6 M19 E2608a-d O2 H7 M19 E2609a-d O2 H8 M19E2610a-d O2 H9 M19 E2611a-d O3 H1 M19 E2612a-d O3 H2 M19 E2613a-d O3 H3M19 E2614a-d O3 H4 M19 E2615a-d O3 H5 M19 E2616a-d O3 H6 M19 E2617a-d O3H7 M19 E2618a-d O3 H8 M19 E2619a-d O3 H9 M19 E2620a-d O4 H1 M19 E2621a-dO4 H2 M19 E2622a-d O4 H3 M19 E2623a-d O4 H4 M19 E2624a-d O4 H5 M19E2625a-d O4 H6 M19 E2626a-d O4 H7 M19 E2627a-d O4 H8 M19 E2628a-d O4 H9M19 E2629a-d O5 H1 M19 E2630a-d O5 H2 M19 E2631a-d O5 H3 M19 E2632a-d O5H4 M19 E2633a-d O5 H5 M19 E2634a-d O5 H6 M19 E2635a-d O5 H7 M19 E2636a-dO5 H8 M19 E2637a-d O5 H9 M19 E2638a-d O6 H1 M19 E2639a-d O6 H2 M19E2640a-d O6 H3 M19 E2641a-d O6 H4 M19 E2642a-d O6 H5 M19 E2643a-d O6 H6M19 E2644a-d O6 H7 M19 E2645a-d O6 H8 M19 E2646a-d O6 H9 M19 E2647a-d O7H1 M19 E2648a-d O7 H2 M19 E2649a-d O7 H3 M19 E2650a-d O7 H4 M19 E2651a-dO7 H5 M19 E2652a-d O7 H6 M19 E2653a-d O7 H7 M19 E2654a-d O7 H8 M19E2655a-d O7 H9 M19 E2656a-d O8 H1 M19 E2657a-d O8 H2 M19 E2658a-d O8 H3M19 E2659a-d O8 H4 M19 E2660a-d O8 H5 M19 E2661a-d O8 H6 M19 E2662a-d O8H7 M19 E2663a-d O8 H8 M19 E2664a-d O8 H9 M19 E2665a-d O9 H1 M19 E2666a-dO9 H2 M19 E2667a-d O9 H3 M19 E2668a-d O9 H4 M19 E2669a-d O9 H5 M19E2670a-d O9 H6 M19 E2671a-d O9 H7 M19 E2672a-d O9 H8 M19 E2673a-d O9 H9M19 E2674a-d O10 H1 M19 E2675a-d O10 H2 M19 E2676a-d O10 H3 M19 E2677a-dO10 H4 M19 E2678a-d O10 H5 M19 E2679a-d O10 H6 M19 E2680a-d O10 H7 M19E2681a-d O10 H8 M19 E2682a-d O10 H9 M19 E2683a-d O11 H1 M19 E2684a-d O11H2 M19 E2685a-d O11 H3 M19 E2686a-d O11 H4 M19 E2687a-d O11 H5 M19E2688a-d O11 H6 M19 E2689a-d O11 H7 M19 E2690a-d O11 H8 M19 E2691a-d O11H9 M19 E2692a-d O12 H1 M19 E2693a-d O12 H2 M19 E2694a-d O12 H3 M19E2695a-d O12 H4 M19 E2696a-d O12 H5 M19 E2697a-d O12 H6 M19 E2698a-d O12H7 M19 E2699a-d O12 H8 M19 E2700a-d O12 H9 M19 E2701a-d O13 H1 M19E2702a-d O13 H2 M19 E2703a-d O13 H3 M19 E2704a-d O13 H4 M19 E2705a-d O13H5 M19 E2706a-d O13 H6 M19 E2707a-d O13 H7 M19 E2708a-d O13 H8 M19E2709a-d O13 H9 M19 E2710a-d O14 H1 M19 E2711a-d O14 H2 M19 E2712a-d O14H3 M19 E2713a-d O14 H4 M19 E2714a-d O14 H5 M19 E2715a-d O14 H6 M19E2716a-d O14 H7 M19 E2717a-d O14 H8 M19 E2718a-d O14 H9 M19 E2719a-d O15H1 M19 E2720a-d O15 H2 M19 E2721a-d O15 H3 M19 E2722a-d O15 H4 M19E2723a-d O15 H5 M19 E2724a-d O15 H6 M19 E2725a-d O15 H7 M19 E2726a-d O15H8 M19 E2727a-d O15 H9 M19 E2728a-d O16 H1 M19 E2729a-d O16 H2 M19E2730a-d O16 H3 M19 E2731a-d O16 H4 M19 E2732a-d O16 H5 M19 E2733a-d O16H6 M19 E2734a-d O16 H7 M19 E2735a-d O16 H8 M19 E2736a-d O16 H9 M19E2737a-d O1 H1 M20 E2738a-d O1 H2 M20 E2739a-d O1 H3 M20 E2740a-d O1 H4M20 E2741a-d O1 H5 M20 E2742a-d O1 H6 M20 E2743a-d O1 H7 M20 E2744a-d O1H8 M20 E2745a-d O1 H9 M20 E2746a-d O2 H1 M20 E2747a-d O2 H2 M20 E2748a-dO2 H3 M20 E2749a-d O2 H4 M20 E2750a-d O2 H5 M20 E2751a-d O2 H6 M20E2752a-d O2 H7 M20 E2753a-d O2 H8 M20 E2754a-d O2 H9 M20 E2755a-d O3 H1M20 E2756a-d O3 H2 M20 E2757a-d O3 H3 M20 E2758a-d O3 H4 M20 E2759a-d O3H5 M20 E2760a-d O3 H6 M20 E2761a-d O3 H7 M20 E2762a-d O3 H8 M20 E2763a-dO3 H9 M20 E2764a-d O4 H1 M20 E2765a-d O4 H2 M20 E2766a-d O4 H3 M20E2767a-d O4 H4 M20 E2768a-d O4 H5 M20 E2769a-d O4 H6 M20 E2770a-d O4 H7M20 E2771a-d O4 H8 M20 E2772a-d O4 H9 M20 E2773a-d O5 H1 M20 E2774a-d O5H2 M20 E2775a-d O5 H3 M20 E2776a-d O5 H4 M20 E2777a-d O5 H5 M20 E2778a-dO5 H6 M20 E2779a-d O5 H7 M20 E2780a-d O5 H8 M20 E2781a-d O5 H9 M20E2782a-d O6 H1 M20 E2783a-d O6 H2 M20 E2784a-d O6 H3 M20 E2785a-d O6 H4M20 E2786a-d O6 H5 M20 E2787a-d O6 H6 M20 E2788a-d O6 H7 M20 E2789a-d O6H8 M20 E2790a-d O6 H9 M20 E2791a-d O7 H1 M20 E2792a-d O7 H2 M20 E2793a-dO7 H3 M20 E2794a-d O7 H4 M20 E2795a-d O7 H5 M20 E2796a-d O7 H6 M20E2797a-d O7 H7 M20 E2798a-d O7 H8 M20 E2799a-d O7 H9 M20 E2800a-d O8 H1M20 E2801a-d O8 H2 M20 E2802a-d O8 H3 M20 E2803a-d O8 H4 M20 E2804a-d O8H5 M20 E2805a-d O8 H6 M20 E2806a-d O8 H7 M20 E2807a-d O8 H8 M20 E2808a-dO8 H9 M20 E2809a-d O9 H1 M20 E2810a-d O9 H2 M20 E2811a-d O9 H3 M20E2812a-d O9 H4 M20 E2813a-d O9 H5 M20 E2814a-d O9 H6 M20 E2815a-d O9 H7M20 E2816a-d O9 H8 M20 E2817a-d O9 H9 M20 E2818a-d O10 H1 M20 E2819a-dO10 H2 M20 E2820a-d O10 H3 M20 E2821a-d O10 H4 M20 E2822a-d O10 H5 M20E2823a-d O10 H6 M20 E2824a-d O10 H7 M20 E2825a-d O10 H8 M20 E2826a-d O10H9 M20 E2827a-d O11 H1 M20 E2828a-d O11 H2 M20 E2829a-d O11 H3 M20E2830a-d O11 H4 M20 E2831a-d O11 H5 M20 E2832a-d O11 H6 M20 E2833a-d O11H7 M20 E2834a-d O11 H8 M20 E2835a-d O11 H9 M20 E2836a-d O12 H1 M20E2837a-d O12 H2 M20 E2838a-d O12 H3 M20 E2839a-d O12 H4 M20 E2840a-d O12H5 M20 E2841a-d O12 H6 M20 E2842a-d O12 H7 M20 E2843a-d O12 H8 M20E2844a-d O12 H9 M20 E2845a-d O13 H1 M20 E2846a-d O13 H2 M20 E2847a-d O13H3 M20 E2848a-d O13 H4 M20 E2849a-d O13 H5 M20 E2850a-d O13 H6 M20E2851a-d O13 H7 M20 E2852a-d O13 H8 M20 E2853a-d O13 H9 M20 E2854a-d O14H1 M20 E2855a-d O14 H2 M20 E2856a-d O14 H3 M20 E2857a-d O14 H4 M20E2858a-d O14 H5 M20 E2859a-d O14 H6 M20 E2860a-d O14 H7 M20 E2861a-d O14H8 M20 E2862a-d O14 H9 M20 E2863a-d O15 H1 M20 E2864a-d O15 H2 M20E2865a-d O15 H3 M20 E2866a-d O15 H4 M20 E2867a-d O15 H5 M20 E2868a-d O15H6 M20 E2869a-d O15 H7 M20 E2870a-d O15 H8 M20 E2871a-d O15 H9 M20E2872a-d O16 H1 M20 E2873a-d O16 H2 M20 E2874a-d O16 H3 M20 E2875a-d O16H4 M20 E2876a-d O16 H5 M20 E2877a-d O16 H6 M20 E2878a-d O16 H7 M20E2879a-d O16 H8 M20 E2880a-d O16 H9 M20 E2881a-d O1 H1 M21 E2882a-d O1H2 M21 E2883a-d O1 H3 M21 E2884a-d O1 H4 M21 E2885a-d O1 H5 M21 E2886a-dO1 H6 M21 E2887a-d O1 H7 M21 E2888a-d O1 H8 M21 E2889a-d O1 H9 M21E2890a-d O2 H1 M21 E2891a-d O2 H2 M21 E2892a-d O2 H3 M21 E2893a-d O2 H4M21 E2894a-d O2 H5 M21 E2895a-d O2 H6 M21 E2896a-d O2 H7 M21 E2897a-d O2H8 M21 E2898a-d O2 H9 M21 E2899a-d O3 H1 M21 E2900a-d O3 H2 M21 E2901a-dO3 H3 M21 E2902a-d O3 H4 M21 E2903a-d O3 H5 M21 E2904a-d O3 H6 M21E2905a-d O3 H7 M21 E2906a-d O3 H8 M21 E2907a-d O3 H9 M21 E2908a-d O4 H1M21 E2909a-d O4 H2 M21 E2910a-d O4 H3 M21 E2911a-d O4 H4 M21 E2912a-d O4H5 M21 E2913a-d O4 H6 M21 E2914a-d O4 H7 M21 E2915a-d O4 H8 M21 E2916a-dO4 H9 M21 E2917a-d O5 H1 M21 E2918a-d O5 H2 M21 E2919a-d O5 H3 M21E2920a-d O5 H4 M21 E2921a-d O5 H5 M21 E2922a-d O5 H6 M21 E2923a-d O5 H7M21 E2924a-d O5 H8 M21 E2925a-d O5 H9 M21 E2926a-d O6 H1 M21 E2927a-d O6H2 M21 E2928a-d O6 H3 M21 E2929a-d O6 H4 M21 E2930a-d O6 H5 M21 E2931a-dO6 H6 M21 E2932a-d O6 H7 M21 E2933a-d O6 H8 M21 E2934a-d O6 H9 M21E2935a-d O7 H1 M21 E2936a-d O7 H2 M21 E2937a-d O7 H3 M21 E2938a-d O7 H4M21 E2939a-d O7 H5 M21 E2940a-d O7 H6 M21 E2941a-d O7 H7 M21 E2942a-d O7H8 M21 E2943a-d O7 H9 M21 E2944a-d O8 H1 M21 E2945a-d O8 H2 M21 E2946a-dO8 H3 M21 E2947a-d O8 H4 M21 E2948a-d O8 H5 M21 E2949a-d O8 H6 M21E2950a-d O8 H7 M21 E2951a-d O8 H8 M21 E2952a-d O8 H9 M21 E2953a-d O9 H1M21 E2954a-d O9 H2 M21 E2955a-d O9 H3 M21 E2956a-d O9 H4 M21 E2957a-d O9H5 M21 E2958a-d O9 H6 M21 E2959a-d O9 H7 M21 E2960a-d O9 H8 M21 E2961a-dO9 H9 M21 E2962a-d O10 H1 M21 E2963a-d O10 H2 M21 E2964a-d O10 H3 M21E2965a-d O10 H4 M21 E2966a-d O10 H5 M21 E2967a-d O10 H6 M21 E2968a-d O10H7 M21 E2969a-d O10 H8 M21 E2970a-d O10 H9 M21 E2971a-d O11 H1 M21E2972a-d O11 H2 M21 E2973a-d O11 H3 M21 E2974a-d O11 H4 M21 E2975a-d O11H5 M21 E2976a-d O11 H6 M21 E2977a-d O11 H7 M21 E2978a-d O11 H8 M21E2979a-d O11 H9 M21 E2980a-d O12 H1 M21 E2981a-d O12 H2 M21 E2982a-d O12H3 M21 E2983a-d O12 H4 M21 E2984a-d O12 H5 M21 E2985a-d O12 H6 M21E2986a-d O12 H7 M21 E2987a-d O12 H8 M21 E2988a-d O12 H9 M21 E2989a-d O13H1 M21 E2990a-d O13 H2 M21 E2991a-d O13 H3 M21 E2992a-d O13 H4 M21E2993a-d O13 H5 M21 E2994a-d O13 H6 M21 E2995a-d O13 H7 M21 E2996a-d O13H8 M21 E2997a-d O13 H9 M21 E2998a-d O14 H1 M21 E2999a-d O14 H2 M21E3000a-d O14 H3 M21 E3001a-d O14 H4 M21 E3002a-d O14 H5 M21 E3003a-d O14H6 M21 E3004a-d O14 H7 M21 E3005a-d O14 H8 M21 E3006a-d O14 H9 M21E3007a-d O15 H1 M21 E3008a-d O15 H2 M21 E3009a-d O15 H3 M21 E3010a-d O15H4 M21 E3011a-d O15 H5 M21 E3012a-d O15 H6 M21 E3013a-d O15 H7 M21E3014a-d O15 H8 M21 E3015a-d O15 H9 M21 E3016a-d O16 H1 M21 E3017a-d O16H2 M21 E3018a-d O16 H3 M21 E3019a-d O16 H4 M21 E3020a-d O16 H5 M21E3921a-d O16 H6 M21 E3022a-d O16 H7 M21 E3023a-d O16 H8 M21 E3024a-d O16H9 M21 E3025a-d O1 H1 M22 E3026a-d O1 H2 M22 E3027a-d O1 H3 M22 E3028a-dO1 H4 M22 E3029a-d O1 H5 M22 E3030a-d O1 H6 M22 E3031a-d O1 H7 M22E3032a-d O1 H8 M22 E3033a-d O1 H9 M22 E3034a-d O2 H1 M22 E3035a-d O2 H2M22 E3036a-d O2 H3 M22 E3037a-d O2 H4 M22 E3038a-d O2 H5 M22 E3039a-d O2H6 M22 E3040a-d O2 H7 M22 E3041a-d O2 H8 M22 E3042a-d O2 H9 M22 E3043a-dO3 H1 M22 E3044a-d O3 H2 M22 E3045a-d O3 H3 M22 E3046a-d O3 H4 M22E3047a-d O3 H5 M22 E3048a-d O3 H6 M22 E3049a-d O3 H7 M22 E3050a-d O3 H8M22 E3051a-d O3 H9 M22 E3052a-d O4 H1 M22 E3053a-d O4 H2 M22 E3054a-d O4H3 M22 E3055a-d O4 H4 M22 E3056a-d O4 H5 M22 E3057a-d O4 H6 M22 E3058a-dO4 H7 M22 E3059a-d O4 H8 M22 E3060a-d O4 H9 M22 E3061a-d O5 H1 M22E3062a-d O5 H2 M22 E3063a-d O5 H3 M22 E3064a-d O5 H4 M22 E3065a-d O5 H5M22 E3066a-d O5 H6 M22 E3067a-d O5 H7 M22 E3068a-d O5 H8 M22 E3069a-d O5H9 M22 E3070a-d O6 H1 M22 E3071a-d O6 H2 M22 E3072a-d O6 H3 M22 E3073a-dO6 H4 M22 E3074a-d O6 H5 M22 E3075a-d O6 H6 M22 E3076a-d O6 H7 M22E3077a-d O6 H8 M22 E3078a-d O6 H9 M22 E3079a-d O7 H1 M22 E3080a-d O7 H2M22 E3081a-d O7 H3 M22 E3082a-d O7 H4 M22 E3083a-d O7 H5 M22 E3084a-d O7H6 M22 E3085a-d O7 H7 M22 E3086a-d O7 H8 M22 E3087a-d O7 H9 M22 E3088a-dO8 H1 M22 E3089a-d O8 H2 M22 E3090a-d O8 H3 M22 E3091a-d O8 H4 M22E3092a-d O8 H5 M22 E3093a-d O8 H6 M22 E3094a-d O8 H7 M22 E3095a-d O8 H8M22 E3096a-d O8 H9 M22 E3097a-d O9 H1 M22 E3098a-d O9 H2 M22 E3099a-d O9H3 M22 E3100a-d O9 H4 M22 E3101a-d O9 H5 M22 E3102a-d O9 H6 M22 E3103a-dO9 H7 M22 E3104a-d O9 H8 M22 E3105a-d O9 H9 M22 E3106a-d O10 H1 M22E3107a-d O10 H2 M22 E3108a-d O10 H3 M22 E3109a-d O10 H4 M22 E3110a-d O10H5 M22 E3111a-d O10 H6 M22 E3112a-d O10 H7 M22 E3113a-d O10 H8 M22E3114a-d O10 H9 M22 E3115a-d O11 H1 M22 E3116a-d O11 H2 M22 E3117a-d O11H3 M22 E3118a-d O11 H4 M22 E3119a-d O11 H5 M22 E3120a-d O11 H6 M22E3121a-d O11 H7 M22 E3122a-d O11 H8 M22 E3123a-d O11 H9 M22 E3124a-d O12H1 M22 E3125a-d O12 H2 M22 E3126a-d O12 H3 M22 E3127a-d O12 H4 M22E3128a-d O12 H5 M22 E3129a-d O12 H6 M22 E3130a-d O12 H7 M22 E3131a-d O12H8 M22 E3132a-d O12 H9 M22 E3133a-d O13 H1 M22 E3134a-d O13 H2 M22E3135a-d O13 H3 M22 E3136a-d O13 H4 M22 E3137a-d O13 H5 M22 E3138a-d O13H6 M22 E3139a-d O13 H7 M22 E3140a-d O13 H8 M22 E3141a-d O13 H9 M22E3142a-d O14 H1 M22 E3143a-d O14 H2 M22 E3144a-d O14 H3 M22 E3145a-d O14H4 M22 E3146a-d O14 H5 M22 E3147a-d O14 H6 M22 E3148a-d O14 H7 M22E3149a-d O14 H8 M22 E3150a-d O14 H9 M22 E3151a-d O15 H1 M22 E3152a-d O15H2 M22 E3153a-d O15 H3 M22 E3154a-d O15 H4 M22 E3155a-d O15 H5 M22E3156a-d O15 H6 M22 E3157a-d O15 H7 M22 E3158a-d O15 H8 M22 E3159a-d O15H9 M22 E3160a-d O16 H1 M22 E3161a-d O16 H2 M22 E3162a-d O16 H3 M22E3163a-d O16 H4 M22 E3164a-d O16 H5 M22 E3165a-d O16 H6 M22 E3166a-d O16H7 M22 E3167a-d O16 H8 M22 E3168a-d O16 H9 M223. Synthesis of the Compounds of the Invention

In another aspect, the invention provides methods for making thecompounds of the invention. The following schemes depict some exemplarychemistries available for synthesizing the compounds of the invention.It will be appreciated, however, that the desired compounds may besynthesized using other alternative chemistries known in the art.

Scheme 1 illustrates the synthesis of oxazolidinones substituted at C-5with 1,2,3-triazolylmethyl derivatives. Isocyanates 14 can react withlithium bromide and glycidyl butyrate at elevated temperature to produceoxazolidinone intermediates of type 15 (Gregory et al. (1989) J. MED.CHEM. 32: 1673). Hydrolysis of the resulting butyrate ester of compound15 produces alcohol 17. Alcohol 17 can also be synthesized fromcarbamates such as the benzyl carbamate 16. The carbamate nitrogen ofcompound 16 then is deprotonated, and alkylated with glycidyl butyrateto produce (after in situ hydrolysis of the butyl ester) hydroxymethylderivative 17. While the R enantiomer depicted throughout Scheme 1generally is the most biologically useful derivative for antibacterialagents, it is contemplated that compounds derived from either the R orthe S enantiomer, or any mixture of R and S enantiomers, may be usefulin the practice of the invention.

Alcohols 17 can be converted to useful intermediates such as mesylates18a (by treatment with methanesulfonyl chloride and triethylamine in anappropriate solvent) and azide 19 (by subsequent displacement of themesylate by sodium azide in DMF). Azide 19 can also be produced fromtosylate 18b (or a brosylate or nosylate), or an alkyl halide of type18c (made from alcohol 17 via methods known to those skilled in theart). Azide 19 can be heated in the presence of substituted acetylenes20 to produce C-5 substituted 1,2,3-triazolylmethyl oxazolidinonederivatives of type 21 and 22. It is to be understood that alternativechemical conditions could be employed by those skilled in the art toeffect this transformation.

It is understood that unsymmetrical acetylene derivatives can react toproduce a mixture of regioisomeric cycloaddition products, representedby 21 and 22, and that the reaction conditions can be adjusted byprocesses known to those skilled in the art to produce more selectivelyone regioisomer or the other. For example, Scheme 2 depicts the reactionof mono-substituted acetylene 23 with azide 19 to produce tworegioisomeric triazoles, 24 and 25. The major isomer is most often theanti isomer 24 since the reaction leading to this product proceeds at afaster rate. Under certain circumstances, the more sterically disfavoredsyn isomer is also formed, but at an appreciably diminished rate. Theaddition of copper(I)iodide is a useful additive for this reaction, andoften leads to increased proportions of the major “anti” adduct 24(Tornoe, C. W. et al. (2002) J. ORG. CHEM. 67: 3057). Increasedproportions of the minor isomer 25 may be produced by minor modificationof the reaction scheme. Azide 19 can react with the trimethylsilylsubstituted acetylene 26 to produce the anti isomer 27 and the synisomer 28. Desilylation with tetrabutylammonium fluoride can producetriazole 24 and 25, with increased proportions of 25 obtainable from themore abundant precursor triazole 27.

An alternate approach toward the synthesis of some of the compounds ofthe present invention is shown in Scheme 3. Aromatic halide 29, whenactivated, can react with the anion derived from treatment of carbamate33 with an appropriate base to produce 3-aryl substituted oxazolidinonederivatives 31 via nucleophilic aromatic substitution. Suitable basesinclude, for example, n-BuLi, LiN(Si(CH₃)₃)₂, and NaH. Carbamate 33 canbe synthesized by exposure of 32 to carbonyldiimidazole in DMF, followedby in situ silylation of the hydroxymethyl group of the initial productwith an appropriate silyl chloride. Desilylation of derivatives of type31 produces alcohols 17 that can be converted to the targets of thepresent invention by the processes described within the schemes.

Scheme 4a illustrates the synthesis of some alkynes of type 23 requiredfor the synthesis of some of the compounds of the present invention.Secondary alkyl amines (or cycloalkyl amines) can be alkylated withelectrophiles comprised of an alkyne connected by a variable bond orlinker to a carbon bearing a leaving group, for example, a halide orsulfonate group (35), to produce alkynes of type 36. The substitutedalkynes can be used in cycloaddition reactions with azides to yieldtriazole-linked target compounds. The amino group undergoing such analkylation can be derived from amino saccharides, for example (but notlimited to), the des-methyl desosamine derivative 37. Desosaminederivative 37 is available from the degradation of erythromycin.Alkylation of 37 with alkynes 35 produces triazole-linked sugarcompounds of type 38. The dimethyl amino group of the desosamine sugarof macrolide antibiotics can be monodemethylated to produce thecorresponding secondary amine (U.S. Pat. No. 3,725,385, Flynn et al.(1954) J. AM. CHEM. SOC. 76: 3121; Ku et al. (1997) BIOORG. MED. CHEM.LETT. 7: 1203; Stenmark et al. (2000) J. ORG. CHEM. 65: 3875). Forexample, amine 39 (an intermediate in the synthesis of amino sugar 37),or a suitably protected derivative of 39 such as the per-silylatedcompound (formed by pre-treatment with bis-trimethylsilylacetamide,hexamethyldisilazane or other agents known in the art) can be alkylatedwith alkynes of type 35. This alkylation reaction produces intermediatesof type 40, that can react with azides of type 19 to yield targetcompounds.

An alternative route is available for the production of desosaminederivatives 38. Alkynes 40 can be hydrolyzed with strong acid to produceamines 38. It is understood that, given appropriate reaction conditionsknown to those skilled in the art, any macrolide antibacterial agent(naturally occurring, semi-synthetic or synthesized) is capable ofserving as starting material for the processes depicted in Scheme 4a.

Scheme 4b illustrates the synthesis of compounds of the presentinvention that contain extra keto groups in the alkyl link between the5-membered heterocyclic ring and the macrolide moiety. Azides 19 canreact with propiolate esters to produce the ester-substituted products.(It is to be understood that mixtures of regioisomeric cycloadducts mayform in this reaction, however, only the anti adduct is depicted inScheme 4b.) Hydrolysis of the ester yields the acid, which can beconverted using known chemistry (Ramtohul et al. (2000) J. ORG. CHEM.67: 3169) to the bromoacetyl triazole. Heating this bromoacetylderivative with 39 (or a suitably protected version of 39) can yieldproducts that contain a keto link with one methylene group between theketone and the macrolide group. The bromoacetyl intermediate can beconverted via lithio-dithiane chemistry, subsequent hydrolysis, andreduction to an alcohol. The tosylate (or halide) of this alcohol can bemade, and this electrophile can be used to alkylate 39 to give productswith two methylene groups between the ketone and the macrolide group.

Scheme 5 illustrates another method to synthesize regioisomerictriazole-linked derivatives of the invention. Carbon-linked triazolederivatives of type 44 and 45 can be produced by first displacing aleaving group (for example, a sulfonate or a halide) from electrophiles18a–c, with either lithium acetylide 41a or lithiumtrimethylsilylacetylide 41b to produce alkynes 42. The cycloadditionreaction of alkynes 42 with appropriate azides 43 can yieldregioisomeric triazoles 44 and 45. (It will be understood thatalternative chemical conditions could be employed to produce compounds44 and 45 such as the use of copper(I)iodide instead of heat).

A specific example of the utility of the chemistry expressed in Scheme 5is shown in Scheme 6. Des-methyl erythromycin derivative 39 (or asuitably protected derivative thereof) can be alkylated with abromoalcohol, and the alcohol function of the product converted to aleaving group such as a tosylate. The tosylate can be displaced withsodium azide to yield azide 46. Cycloadditon of 46 and alkyne 42a canproduce final targets of type 47. Alternative alkylsulfonates or halidescan be used as the starting material for the synthesis of azide 46(i.e., different leaving groups). Other macrolide entities can be usedin place of the des-methyl erythromycin derivative 39 to produce avariety of alternative products.

Another method that can be used to synthesize carbon-linked triazolederivatives of type 47 is illustrated in Scheme 7. Alkyne 42a can reactwith trimethylsilylazide (or with sodium azide, ammonium chloride andcopper(I)iodide, or other conditions known in the art) to produce twopossible regioisomeric products, triazoles 48 and 49. Either of these(or the mixture) can be desilylated with n-Bu₄NF to produce triazole 50.Des-methyl erythromycin derivative 39 (or an alternate des-methyl aminomacrolide derivative) can be converted to tosylate 51 (or anothersulfonate or halide electrophile), and then the electrophile can serveto alkylate triazole 50 to produce either the N-1 substituted triazole47, or the N-2 substituted triazole 53, or a mixture of both. In theevent that a mixture is produced, both compounds may be separated fromone another. It is contemplated that other macrolides may be transformedby the chemistry of Scheme 7 to produce other compounds of interest.

Scheme 8a illustrates the synthesis of oxazolidinones substituted at C-5with tetrazolylmethyl derivatives. Azides of type 19 can react withnitrites 54 to produce tetrazoles of type 55 and 56. In a similarfashion to the chemistry described in Scheme 1, this reaction can yieldregioisomeric cycloadducts, where the anti isomer often predominates. Asan example, des-methyl erythromycin 39 can be alkylated with ω-halo orω-sulfonate nitrites to yield nitrites 57. These derivatives can reactwith azides of type 19 to produce target tetrazoles of type 59 and 60.It is to be understood that the R′ group of nitrites 54 may contain themacrolide moiety, or suitable substituted alkyl groups containing analcohol or protected alcohol that could be converted to a leaving groupprior to a final alkylation step with a macrolide amine. Thus, thetetrazoles 55 and 56 could be produced that have as their R′ groupsalkyl chains bearing a hydroxy group that can be converted into asulfonate or halide leaving group prior to alkylation with aminessimilar to 39 to afford products of type 59 and 60. The hydroxy groupmay be unmasked from a protected hydroxyl group in the compounds 55 and56 prior to further conversions as mentioned above to afford targets oftype 59 and 60.

Scheme 8b depicts another strategy to synthesize tetrazoles of type 59and 60. Azides 19 could undergo cycloaddition to functionalized nitritesof type 57a to afford tetrazole intermediates 55a and 56a. If 55a and56a contain an appropriate electrophilic group such as a halide orsulfonate, it can react directly with macrolide amines of type 39 (or asuitably protected derivative thereof) to yield targets of type 59 and60. Alternatively, silyloxy-substituted nitrites 57a could be usedduring the cycloaddition reaction to afford intermediates of type 55aand 56a where X is a silyloxy group. The silylether protecting groupcould then be removed from 55a and 56a, and the resultant alcoholconverted to an appropriate electrophile (such as a halide or sulfonate)that would then be suitable for alkylation of macrolide amines of type39 to give the desired targets.

It will be understood that if the alkyl group bearing substituent X in55a and 56a contains a hydroxyl group, the group could be oxidized to analdehyde by methods well known to those skilled in the art. Suchaldehydes could be used to produce targets of type 59 and 60 via the useof reductive amination conditions employed on these aldehydes andmacrolide amines similar to amine 39 (or suitably protected variantsthereof).

Scheme 9 illustrates one method of synthesizing pyrazole derivatives ofthe present invention. Known trityl-protected organolithium derivative61 (Elguero et al. (1997) SYNTHESIS 563) can be alkylated withelectrophiles of type 18a–c to produce pyrazoles of type 62. Cleavage ofthe trityl group can be accomplished using a variety of acidic reagents,for example, trifluoroacetic acid (TFA), to produce pyrazole 63.Alkylation of 63 with a bromoalcohol of appropriate length, followed bytosylation (or alternate sulfonation or halide formation) can produceelectrophiles 64. Alkylation of 39 with 64 produces targets of type 65.The lithium anions derived from heterocycles such as 61 may optionallybe converted to copper (or other metallic) derivatives to facilitatetheir displacement reactions with sulfonates and halides. These anionsmay also be allowed to react with suitably protected macrolides, such asthe per-silylated derivative of 51.

Scheme 10 depicts another method of synthesizing pyrazoles of thepresent invention. Anions 61 can be alkylated with a bifunctional linkerof variable length such as an alkyl halide containing a silyloxyderivative. Alternatively an α,ω dihaloalkyl derivative can be used asthe alkylating agent, or a mixed halo-sulfonate can be employed for thispurpose. The resulting substituted pyrazoles 66 can be converted to thefree pyrazoles by TFA cleavage of the triphenylmethyl protecting group.The free pyrazoles can undergo direct alkylation with electrophiles18a–c in a suitable solvent, for example, dimethylformamide, or can befirst converted via deprotonation with a suitable base, for example,sodium hydride or n-butyllithium, to the corresponding anion, if a morereactive nucleophile is required. The resultant pyrazole derivatives 67can be desilylated and converted to tosylates 68 (if a sulfonatestrategy is employed), which can serve as electrophiles for subsequentreaction with macrolide aminosaccharides, for example, amine 39, toproduce the resultant target 69.

Another approach to intermediates of type 67 can start with alkylationof the known dianion 70 (Hahn et al. (1991) J. HETEROCYCLIC CHEMISTRY28: 1189) with an appropriate bifunctional linker to produce compoundsrelated to pyrazole 71, which can subsequently be alkylated (with orwithout prior deprotonation) with electrophiles 18a–c to produceintermediates 67. The n=1 derivatives in this series can be synthesizedby trapment of compound 61 with DMF to produce the correspondingaldehyde, and then reduction to the alcohol. Alternatively,methoxymethyl (MOM) chloride or bromide can serve as the alkylatingreagent for 61, and hydrolysis of the trityl and MOM groups of theproduct would yield 4-hydroxymethyl-1,2-pyrazole. The dianion of thispyrazole can be alkylated on nitrogen to produce an alcohol that servesas the precursor for a n=1 tosylate (or other leaving group).

Scheme 11 shows an alternate approach for synthesizing pyrazolederivatives of type 69. Alkylation of the anion of a β-dicarbonyl systemwith appropriate electrophiles similar to tosylate 51 can yield (in thespecific example of β-dicarbonyl derivative 72a) products of type 73.Treatment of these intermediates with hydrazine can produce pyrazoles oftype 74. Direct alkylation of 74 with electrophiles 18a–c can proceed toproduce targets 69. Alternatively, the hydroxyl residues of 74 (andother sensitive functional groups of other macrolide derivatives such asintermediates 39 and 51) can be protected with suitable protectinggroups (such as those highlighted in Greene, T. W. and Wuts, P. G. M.supra), and the hydrogen atom on the nitrogen atom of the pyrazolederivative deprotonated with a suitable base, for example, sodiumhydride or n-butyllithium. The resulting anion can then be alkylatedwith electrophiles 18a–c, and the resulting product deprotected toproduce targets 69. The use of protecting groups well known to thoseskilled in the art for the macrolide portions of these intermediates maybe required for many of the subsequent reactions shown in the schemesbelow that involve heteroaryl anion alkylations.

Scheme 12 exemplifies a synthesis of imidazoles of the presentinvention. The known dianion 75 (Katritzky et al. (1989) J. CHEM. SOC.PERKIN TRANS. 1: 1139) can react with electrophiles 18a–c to produceafter protic work-up imidazoles of type 76. Direct alkylation of 76 byheating with electrophiles related to 51 in an appropriate organicsolvent can yield 1,4-disubstituted imidazoles 77. Alternatively, theimidazole anion formed via deprotonation of the imidazole hydrogen atomof 76 with a suitable base and then alkylation with 51 can also produce77.

Scheme 13 illustrates another synthesis of imidazoles of the presentinvention. 4-Bromoimidazole can be deprotonated using, for example,sodium hydride or lithium diisopropylamide, or another suitable organicbase, to give anion 78 (or the corresponding lithio derivative).Alkylation of 78 with 18a–c can yield bromoimidazole 79 which can thenbe subjected to metal-halogen exchange and alkylated with 51 (or asuitably protected derivative of 51) to produce isomeric1,4-disubstituted imidazoles 80.

Scheme 14 depicts chemistry suitable for the synthesis of other targetimidazole derivatives. The silylethoxymethyl (SEM) protected imidazolecan be lithiated at C-2 (Shapiro et al. (1995) HETEROCYCLES 41: 215) andcan react with electrophiles 18a–c to produce imidazole intermediates82. Lithiation of imidazole intermediates 82 at C-4 of the imidazole,followed by alkylation with electrophiles of type 51 (or a suitablyprotected version such as the per-silylated derivative), and thendeprotection of the SEM can produce imidazoles 83.

Scheme 15 shows how tosylmethyl isocyanide can be used to makeimidazoles of the present invention (Vanelle et al. (2000) EUR. J. MED.CHEM. 35: 157; Home et al. (1994) HETEROCYCLES 39: 139). Alcohols 17 canbe oxidized to produce aldehydes 85 using an appropriate agent such asthe Dess-Martin periodinane, or oxalylchloride/dimethylsulfoxide/triethylamine (Swem oxidation). A variety ofchromium complexes can also be used for this oxidation, including, forexample, pyridinium dichromate (PDC), pyridinium chlorochromate (PCC),chromium trioxide, and tetrapropylammonium perruthenate. Wittighomologation of 85 can provide aldehyde 86, which can then be convertedby tosylmethyl isocyanide to produce intermediate 87. The reaction of 87with amines 89 (formed via alkylation of amines 39 with bromoalkylphthalimides 88 followed by hydrazine cleavage, or reduction of azides46) can produce imidazoles 77.

Scheme 16 delineates how 1,3 thiazole and 1,3 oxazole derivatives of thepresent invention can be synthesized. Known dibromo thiazoles andoxazoles 90a and 90b can be selectively metallated at C-2 and alkylatedwith electrophiles 18a–c to produce intermediates 91a and 91b (Pinkertonet al. (1972) J. HETEROCYCLIC CHEMISTRY 9: 67). Transmetallation withzinc chloride can be employed in the case of the oxazole anion if theanion displays any tendency to ring open prior to its reaction withcertain electrophiles. The bromo azoles 91 can be metallated to form thecorresponding anion which can undergo alkylation with sulfonates 51 (orthe related halides) to produce the final targets 92. Reordering of thesequence of electrophiles in this process permits access to the isomericthiazoles and oxazoles 93.

Scheme 17 shows the synthesis of 2,5 disubstituted furan and thiophenederivatives of the invention. Commercially available dibromofuran 94aand dibromothiophene 94b can be monolithiated (Cherioux et al. (2001)ADVANCED FUNCTIONAL MATERIALS 11: 305) and alkylated with electrophiles18a–c. The monobromo intermediates obtained from this reaction can belithiated again and then alkylated with electrophiles of type 51 (or aprotected version of 51) to produce the final targets 95.

Scheme 18 depicts the synthesis of 2,4 disubstituted furan and thiophenederivatives of the invention. Commercially available furan aldehyde 96a,and the known thiophene aldehyde 96b, can be reduced to thecorresponding alcohols and the resulting alcohols converted to a leavinggroup such as tosylates 97. Alternate sulfonates and halides can besynthesized and used in this fashion. The tosylates 97 can alkylateamine 39 (or a protected version thereof), and the heteroaryl bromidecan be converted to a suitable organometallic agent (by reagents such asn-BuLi, or i-Pr₂Mg/CuCN). This intermediate organometallic agent can bealkylated with electrophiles 18a–c to produce targets of type 98 wheren=1. As the scheme shows, a reordering of steps can be employedinvolving reduction, silylation, lithiation and then initial alkylationwith 18a–c. Desilylation of the alkylation product, followed bytosylation of the alcohol, provides an intermediate that can then bealkylated with amine 39 to produce targets 98. Simple homologationprotocols, using the reagents depicted in Scheme 18 or others known tothose skilled in the art, can convert the aldehydes 96 to longer chaintosylates such as 99 and 100. The use of these tosylates in thealkylation with 39, and subsequent metal-halogen exchange and alkylationwith 18a–c, can yield compounds of type 98 where n=2 and 3. It will beappreciated that longer chain tosylates can be produced usingchemistries similar to that depicted in Scheme 18, and that otherbifunctional linkers can be used to produce compounds of type 98.

Chemistries similar to that employed above in Scheme 18 can convertknown thiophene aldehyde 101 (Eras et al. (1984) J. HETEROCYCLICCHEMISTRY 21: 215) to produce products of type 104 (Scheme 19). Theknown acid 102 (Wang et al. (1996) TETRAHEDRON 52: 12137) can beconverted to aldehyde 103 by reduction with, for example, borane orlithium aluminum hydride, followed by oxidation of the resultanthydroxymethyl intermediate with, for example, PDC, PCC, or anothersuitable reagent. Aldehyde 103 can then be converted to producecompounds of type 104.

Scheme 20 illustrates the synthesis of 2,5 disubstituted pyrroles of theinvention. The BOC-protected dibromopyrrole 105 can be lithiated andalkylated sequentially (Chen et al. (1987) TETRAHEDRON LETT. 28: 6025;Chen et al. (1992) ORG. SYNTH. 70: 151; and Martina et al. (1991)SYNTHESIS 613), and allowed to react with electrophiles 18a–c and 51 (ora suitably protected analogue of 51) to produce, after final BOCdeprotection with TFA, disubstituted pyrroles of type 106.

Scheme 21 shows the synthesis of 2,4 disubstituted pyrroles of theinvention. Commercially available pyrrole ester 107 can be protectedwith a suitable protecting group, for example, the BOC group, and theester function hydrolyzed to the corresponding acid. The resulting acidcan then be reduced to the alcohol using, for example, borane to yieldan alcohol that can be converted to tosylate 108. Amine 39 (or asuitably protected version of 39, formed for example by silylation ofthe hydroxyl groups with bis-trimethylsilylacetamide or anothersilylating reagent) can be alkylated with tosylate 108 to produce anintermediate bromopyrrole. The bromopyrrole can then be converted to anorganometallic reagent that can then react with electrophiles 18a–c. Theresulting product can then be deprotected with TFA to produce pyrroles109. The alcohol formed after borane reduction of the acid derived from107 can then be homologated to tosylates 110 and 111 by chemistriessimilar to that shown below in Scheme 23. The use of these tosylates inthe alkylation strategy can produce target pyrroles of type 109 wheren=2 and 3.

An alternative approach is to protect the alcohol functions prior totosylation, and perform the alkylation of the organometallic derivedfrom the halopyrrole with 18a–c first. For example, silyloxy derivative112 can be produced from 107, and the organometallic derivative derivedfrom it alkylated with 18a–c to yield silyl ethers 113. Subsequentdesilylation and conversion to tosylates 114 provides an electrophilethat can be used in the alkylation reaction with 39. A final BOCcleavage can then give pyrroles 109. It is understood that the alcoholprecursor of 112 can be homologated, using chemistries similar to thatshown below in Scheme 23 and other schemes) to other alkanols that canbe tosylated for further reactions with amine 39 (or related macrolidederived amines). Furthermore, the alcohol derived from silyl cleavage of113 can serve as the starting material for this type of homologationefforts to produce the alkyl tosylates (or halides) required for makingtargets 109 where n is variable.

Scheme 22 shows the synthesis of isomeric 2,4 disubstituted pyrroles ofthe invention. Commercially available pyrrole acid 115 can be protectedas the BOC derivative, and the acid function reduced to an alcohol,which can then be protected to produce the silyl ether 116.Deprotonation of 116 with n-butyllithium can occur at the 5 position ofthe pyrrole ring, and this anion (or that derived from transmetallationwith an appropriate metal) can be alkylated with electrophiles 18a–c toproduce pyrrole 117. Desilylation of 117, followed by tosylation,alkylation with amine 39, and TFA deprotection of the BOC group canyield pyrroles 119.

Scheme 23 illustrates the synthesis of longer chain tosylates of type123 and 126 used to alkylate amines of type 39 to produce pyrroles 119.The alcohol 120 derived from protection of 115 followed by boranereduction can be oxidized to aldehyde 124. The Wittig reaction ofaldehyde 124 with methoxymethyl triphenylphosphorane is followed by anacid hydrolysis step to produce the homologated aldehyde 121. Reductionand silyl protection can yield 122, which can then be deprotonated,alkylated and then converted to tosylate 123. Aldehyde 124 can undergo aWittig reaction with carbomethoxymethyl triphenylphosphorane. The Wittigproduct then is reduced to an alkanol that can then be silylated toproduce 125. Conversion of 125 to pyrroles 119 can then occur using thesame chemistry employed to provide 119 from 122.

Scheme 24 shows the synthesis of 1,3 disubstituted pyrroles of thepresent invention. The BOC group of 116 can be cleaved to produce freepyrrole 127. Alkylation of 127 (in a suitable organic solvent such asDMF) with 18a–c can produce intermediate 128. The dianion of3-hydroxymethylpyrrole can also be suitable for alkylation with 18a–c toproduce the free hydroxy derivative of silyl ether 128. Conversion ofthe siloxy group to the corresponding tosylate, followed by alkylationwith amines of type 39 can generate the target N-substituted pyrroles129 (where n=1). In a similar fashion, the BOC pyrroles 122 and 125 canbe converted to the tosylates 130 and 131. These tosylates can be usedto produce pyrroles of type 129 (where n=2 and 3). It is understood thatlonger chain alkyl tosylates (and halides) can be produced that canundergo this chemistry to produce pyrroles 129 where n is>3.

Scheme 25 illustrates the use of hydantoin-like groups as the 5-memberedheterocyclic linker between the G groups and the R₁ moieties of thepresent invention. Electrophiles of type 18a–c can alkylate anionsderived from hydantoins to produce compounds of the present invention.For example, 3-substituted hydantoins of type 132 can be purchased andtreated with an appropriate base to generate the corresponding imideanion. The resulting anionscan be alkylated with electrophiles similar(but not limited) to intermediates 18a–c to produce hydantoinderivatives 134. Alternatively, 1-substituted hydantoins of type 133 canbe purchased or prepared, and treated with base and electrophile toyield isomeric hydantoin derivatives 135. It is understood that suchhydantoins can have, for example, at optional locations, thiocarbonylfunctionalities in place of the illustrated carbonyl groups. Suchcompounds can be prepared by treatment of the oxy-hydantoins withLawesson's reagent, elemental sulfur, phosphorus pentasulfide, and otherreagents commonly used in the art to perform this transformation.

Alternatively, such thiohydantoins can be synthesized selectively bysequential synthetic steps known in the art. The R′ group of 132 and 133may represent a protecting group function, for example, benzyl,alkoxybenzyl, benzyloxycarbonyl, t-butoxycarbonyl, that is compatiblewith the alkylation step. Such a protecting group can subsequently beremoved from products 134 and 135, yielding products where the R′ groupis a hydrogen atom. These intermediates can be used to produce varioustarget molecules by their treatment with base and then subsequentexposure to appropriate electrophiles.

A more specific example of the synthesis of hydantoin derivatives of thepresent invention is depicted in Scheme 26. Hydantoin 136 can be treatedwith a mild organic base, for example, sodium hydride, potassiumtertiary-butoxide, cesium, sodium, or potassium carbonate, to producethe N-1 substituted intermediate 137. Deprotonation of 137 with a base,for example, sodium hydride, n-butyllithium, lithiumbis-trimethylsilylamide or lithium diisopropylamide, followed byalkylation with 51 (or a suitably protected derivative of 51) can yieldhydantoin targets of type 138. The isomeric hydantoin derivatives oftype 141 can be synthesized from 136 by initial p-methoxybenzyl (PMB)protection of the N-1 position, followed by alkylation at N-3 with 18a–cand subsequent deprotection of the PMB group with either2,3-dichloro-3,4-dicyano-benzoquinone (DDQ) or hydrogenation will yieldhydantoin intermediates 140. Subsequent alkylation of 140 with 51 cangive compounds 141. Another route to produce intermediates 140 is byformation of the dianion of hydantoin 136. One equivalent of a weak basecan deprotonate the N-1 position of 136. The addition of anotherequivalent of a strong base, for example, n-butyllithium, to the initialanion can deprotonate it again, this time at N-3. Alkylation can occurat the more reactive position (N-3) to again produce hydantoins 140.

Scheme 27 illustrates how isoxazolidinone derivatives of type 515 of thepresent invention can be synthesized. Macrolide 171 (or any othermacrolide amine) can be converted to alkyl azide 510 (where n≧2) via useof an appropriate alkyl halide or sulfonate electrophile of type 511. Avariety of isoxazolidinone derivatives of type 512 (for syntheses ofthese types of derivatives see U.S. Patent Application 20020094984) canbe alkylated with propargyl electrophiles of type 513 to yield alkynesof type 514. The cycloaddition of azides 510 and alkynes 514 yieldstarget isoxazolidinone derivatives 515. It is to be understood thatalternative macrolides and isoxazolidinone derivatives can be used inthis chemistry, and alternate chain lengths of the various electophilescan be utilized to produce other compounds of the present invention. Itis intended that such alternate targets are within the scope of thepresent invention.

In addition to the foregoing, compounds disclosed in the followingpublications, patents and patent applications are suitable intermediatesfor preparation of the compounds of this invention:

Tucker, J. A. et al., J. Med. Chem., 1998, 41, 3727; Gregory, W. A. etal., J. Med. Chem., 1990, 33, 2569; Genin, M. J. et al., J. Med. Chem.,1998, 41, 5144; Brickner, S. J. et al., J. Med. Chem., 1996, 39, 673.Barbachyn, M. R. et al., J. Med. Chem., 1996, 39, 680; Barbachyn, M. R.et al., Bioorg. Med. Chem. Lett., 1996, 6, 1003; Barbachyn, M. R. etal., Bioorg. Med. Chem. Lett., 1996, 6, 1009; Grega, K. C. et al., J.Org Chem., 1995, 60, 5255; Park, C.-H. et al., J. Med. Chem., 1992, 35,1156; Yu, D. et al., Bioorg. Med. Chem. Lett., 2002, 12, 857;Weidner-Wells, M. A. et al., Bioorg. Med. Chem., 2002, 10, 2345; andCacchi, S. et al., Org. Lett., 2001, 3, 2539. U.S. Pat. Nos. 4,801,600;4,948,801; 5,736,545; 6,362,189; 5,523,403; 4,461,773; 6,365,751;6,124,334; 6,239,152; 5,981,528; 6,194,441; 6,147,197; 6,034,069;4,990,602; 6,124,269; and 6,271,383. U.S. Pat. Application 2001/0046992,PCT Application and publications WO96/15130; WO95/14684; WO 99/28317; WO98/01447; WO 98/01446; WO 97/31917; WO 97/27188; WO 97/10223; WO97/09328; WO 01/46164; WO 01/09107; WO 00/73301; WO 00/21960; WO01/81350; WO 97/30995; WO 99/10342; WO 99/10343; WO 99/64416; WO00/232917; and WO 99/64417, European Patents BP 0312000 B1; EP 0359418A1; EP 00345627; EP 1132392; and BP 0738726 A1.

4. Characterization of Compounds of the Invention

Compounds designed, selected and/or optimized by methods describedabove, once produced, may be characterized using a variety of assaysknown to those skilled in the art to determine whether the compoundshave biological activity. For example, the molecules may becharacterized by conventional assays, including but not limited to thoseassays described below, to determine whether they have a predictedactivity, binding activity and/or binding specificity.

Furthermore, high-throughput screening may be used to speed up analysisusing such assays. As a result, it may be possible to rapidly screen themolecules described herein for activity, for example, as anti-cancer,anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. Also,it may be possible to assay how the compounds interact with a ribosomeor ribosomal subunit and/or are effective as modulators (for example,inhibitors) of protein synthesis using techniques known in the art.General methodologies for performing high-throughput screening aredescribed, for example, in Devlin (1998) High Throughput Screening,Marcel Dekker; and U.S. Pat. No. 5,763,263. High-throughput assays canuse one or more different assay techniques including, but not limitedto, those described below.

(1) Surface Binding Studies. A variety of binding assays may be usefulin screening new molecules for their binding activity. One approachincludes surface plasmon resonance (SPR) which can be used to evaluatethe binding properties molecules of interest with respect to a ribosome,ribosomal subunit or a fragment thereof.

SPR methodologies measure the interaction between two or moremacromolecules in real-time through the generation of aquantum-mechanical surface plasmon. One device, (BIAcore Biosensor RTMfrom Pharmacia Biosensor, Piscatawy, N.J.) provides a focused beam ofpolychromatic light to the interface between a gold film (provided as adisposable biosensor “chip”) and a buffer compartment that can beregulated by the user. A 100 nm thick “hydrogel” composed ofcarboxylated dextran which provides a matrix for the covalentimmobilization of analytes of interest is attached to the gold film.When the focused light interacts with the free electron cloud of thegold film, plasmon resonance is enhanced. The resulting reflected lightis spectrally depleted in wavelengths that optimally evolved theresonance. By separating the reflected polychromatic light into itscomponent wavelengths (by means of a prism), and determining thefrequencies which are depleted, the BIAcore establishes an opticalinterface which accurately reports the behavior of the generated surfaceplasmon resonance. When designed as above, the plasmon resonance (andthus the depletion spectrum) is sensitive to mass in the evanescentfield (which corresponds roughly to the thickness of the hydrogel). Ifone component of an interacting pair is immobilized to the hydrogel, andthe interacting partner is provided through the buffer compartment, theinteraction between the two components can be measured in real timebased on the accumulation of mass in the evanescent field and itscorresponding effects of the plasmon resonance as measured by thedepletion spectrum. This system permits rapid and sensitive real-timemeasurement of the molecular interactions without the need to labeleither component.

(2) Fluorescence Polarization. Fluorescence polarization (FP) is ameasurement technique that can readily be applied to protein-protein,protein-ligand, or RNA-ligand interactions in order to derive IC₅₀s andKds of the association reaction between two molecules. In this techniqueone of the molecules of interest is conjugated with a fluorophore. Thisis generally the smaller molecule in the system (in this case, thecompound of interest). The sample mixture, containing both theligand-probe conjugate and the ribosome, ribosomal subunit or fragmentthereof, is exited with vertically polarized light. Light is absorbed bythe probe fluorophores, and re-emitted a short time later. The degree ofpolarization of the emitted light is measured. Polarization of theemitted light is dependent on several factors, but most importantly onviscosity of the solution and on the apparent molecular weight of thefluorophore. With proper controls, changes in the degree of polarizationof the emitted light depends only on changes in the apparent molecularweight of the fluorophore, which in-turn depends on whether theprobe-ligand conjugate is free in solution, or is bound to a receptor.Binding assays based on FP have a number of important advantages,including the measurement of IC₅₀s and Kds under true homogenousequilibrium conditions, speed of analysis and amenity to automation, andability to screen in cloudy suspensions and colored solutions.

(3) Protein Synthesis. It is contemplated that, in addition tocharacterization by the foregoing biochemical assays, the compound ofinterest may also be characterized as a modulator (for example, aninhibitor of protein synthesis) of the functional activity of theribosome or ribosomal subunit.

Furthermore, more specific protein synthesis inhibition assays may beperformed by administering the compound to a whole organism, tissue,organ, organelle, cell, a cellular or subcellular extract, or a purifiedribosome preparation and observing its pharmacological and inhibitoryproperties by determining, for example, its inhibition constant (IC₅₀)for inhibiting protein synthesis. Incorporation of ³H leucine or ³⁵Smethionine, or similar experiments can be performed to investigateprotein synthesis activity. A change in the amount or the rate ofprotein synthesis in the cell in the presence of a molecule of interestindicates that the molecule is a modulator of protein synthesis. Adecrease in the rate or the amount of protein synthesis indicates thatthe molecule is a inhibitor of protein synthesis.

Furthermore, the compounds may be assayed for anti-proliferative oranti-infective properties on a cellular level. For example, where thetarget organism is a micro-organism, the activity of compounds ofinterest may be assayed by growing the micro-organisms of interest inmedia either containing or lacking the compound. Growth inhibition maybe indicative that the molecule may be acting as a protein synthesisinhibitor. More specifically, the activity of the compounds of interestagainst bacterial pathogens may be demonstrated by the ability of thecompound to inhibit growth of defined strains of human pathogens. Forthis purpose, a panel of bacterial strains can be assembled to include avariety of target pathogenic species, some containing resistancemechanisms that have been characterized. Use of such a panel oforganisms permits the determination of structure-activity relationshipsnot only in regards to potency and spectrum, but also with a view toobviating resistance mechanisms. The assays may be performed inmicrotiter trays according to conventional methodologies as published byThe National Committee for Clinical Laboratory Standards (NCCLS)guidelines (NCCLS. M7-A5-Methods for Dilution AntimicrobialSusceptibility Tests for Bacteria That Grow Aerobically; ApprovedStandard-Fifth Edition. NCCLS Document M100-S12/M7 (ISBN 1-56238-394-9).

The compounds may be assayed for anti-inflammatory properties on acellular level, for example, to determine the inhibition of cytokineproduction. Further, the compounds may be assessed for calcium flux inCHO cells expressing the human motilin receptor or in animal models forprokinetic behavior such as the rabbit duodenum strip model known todisplay contractility when a motilin agonist is applied.

5. Formulation and Administration

The compounds of the invention may be useful in the prevention ortreatment of a variety of human or other animal disorders, including forexample, bacterial infection, fungal infections, viral infections,parasitic diseases, and cancer. It is contemplated that, onceidentified, the active molecules of the invention may be incorporatedinto any suitable carrier prior to use. The dose of active molecule,mode of administration and use of suitable carrier will depend upon theintended recipient and target organism. The formulations, both forveterinary and for human medical use, of compounds according to thepresent invention typically include such compounds in association with apharmaceutically acceptable carrier.

The carrier(s) should be “acceptable” in the sense of being compatiblewith the other ingredients of the formulations and not deleterious tothe recipient. Pharmaceutically acceptable carriers, in this regard, areintended to include any and all solvents, dispersion media, coatings,anti-bacterial and anti-fungal agents, isotonic and absorption delayingagents, and the like, compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances isknown in the art. Except insofar as any conventional media or agent isincompatible with the active compound, use thereof in the compositionsis contemplated. Supplementary active compounds (identified or designedaccording to the invention and/or known in the art) also can beincorporated into the compositions. The formulations may conveniently bepresented in dosage unit from and may be prepared by any of the methodswell known in the art of pharmacy/microbiology. In general, someformulations are prepared by bringing the compound into association witha liquid carrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

A pharmaceutical composition of the invention should be formulated to becompatible with its intended route of administration. Examples of routesof administration include oral or parenteral, for example, intravenous,intradermal, inhalation, transdermal (topical), transmucosal, and rectaladministration. Solutions or suspensions used for parenteral,intradermal, or subcutaneous application can include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. pH can beadjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide.

Useful solutions for oral or parenteral administration can be preparedby any of the methods well known in the pharmaceutical art, described,for example, in Remington's Pharmaceutical Sciences, (Gennaro, A., ed.),Mack Pub., (1990). Formulations for parenteral administration can alsoinclude glycocholate for buccal administration, methoxysalicylate forrectal administration, or citric acid for vaginal administration. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic. Suppositories forrectal administration also can be prepared by mixing the drug with anon-irritating excipient such as cocoa butter, other glycerides, orother compositions which are solid at room temperature and liquid atbody temperatures. Formulations also can include, for example,polyalkylene glycols such as polyethylene glycol, oils of vegetableorigin, hydrogenated naphthalenes, and the like. Formulations for directadministration can include glycerol and other compositions of highviscosity. Other potentially useful parenteral carriers for these drugsinclude ethylene-vinyl acetate copolymer particles, osmotic pumps,implantable infusion systems, and liposomes. Formulations for inhalationadministration can contain as excipients, for example, lactose, or canbe aqueous solutions containing, for example, polyoxyethylene-9-laurylether, glycocholate and deoxycholate, or oily solutions foradministration in the form of nasal drops, or as a gel to be appliedintranasally. Retention enemas also can be used for rectal delivery.

Formulations of the present invention suitable for oral administrationmay be in the form of: discrete units such as capsules, gelatincapsules, sachets, tablets, troches, or lozenges, each containing apredetermined amount of the drug; a powder or granular composition; asolution or a suspension in an aqueous liquid or non-aqueous liquid; oran oil-in-water emulsion or a water-in-oil emulsion. The drug may alsobe administered in the form of a bolus, electuary or paste. A tablet maybe made by compressing or moulding the drug optionally with one or moreaccessory ingredients. Compressed tablets may be prepared bycompressing, in a suitable machine, the drug in a free-flowing form suchas a powder or granules, optionally mixed by a binder, lubricant, inertdiluent, surface active or dispersing agent. Moulded tablets may be madeby moulding, in a suitable machine, a mixture of the powdered drug andsuitable carrier moistened with an inert liquid diluent.

Oral compositions generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients. Oral compositions preparedusing a fluid carrier for use as a mouthwash include the compound in thefluid carrier and are applied orally and swished and expectorated orswallowed. Pharmaceutically compatible binding agents, and/or adjuvantmaterials can be included as part of the composition. The tablets,pills, capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose; a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorELTM (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). Itshould be stable under the conditions of manufacture and storage andshould be preserved against the contaminating action of microorganismssuch as bacteria and fungi. The carrier can be a solvent or dispersionmedium containing, for example, water, ethanol, polyol (for exampleglycerol, propylene glycol, and liquid poletheylene glycol, and thelike), and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case of dispersionand by the use of surfactants. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, polyalcohols such asmanitol, sorbitol, sodium chloride in the composition. Prolongedabsorption of the injectable compositions can be brought about byincluding in the composition an agent which delays absorption, forexample, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfilter sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation include vacuumdrying and freeze-drying which yields a powder of the active ingredientplus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Formulations suitable for intra-articular administration may be in theform of a sterile aqueous preparation of the drug which may be inmicrocrystalline form, for example, in the form of an aqueousmicrocrystalline suspension. Liposomal formulations or biodegradablepolymer systems may also be used to present the drug for bothintra-articular and ophthalmic administration.

Formulations suitable for topical administration, including eyetreatment, include liquid or semi-liquid preparations such as liniments,lotions, gels, applicants, oil-in-water or water-in-oil emulsions suchas creams, ointments or pastes; or solutions or suspensions such asdrops. Formulations for topical administration to the skin surface canbe prepared by dispersing the drug with a dermatologically acceptablecarrier such as a lotion, cream, ointment or soap. Particularly usefulare carriers capable of forming a film or layer over the skin tolocalize application and inhibit removal. For topical administration tointernal tissue surfaces, the agent can be dispersed in a liquid tissueadhesive or other substance known to enhance adsorption to a tissuesurface. For example, hydroxypropylcellulose or fibrinogen/thrombinsolutions can be used to advantage. Alternatively, tissue-coatingsolutions, such as pectin-containing formulations can be used.

For inhalation treatments, inhalation of powder (self-propelling orspray formulations) dispensed with a spray can, a nebulizer, or anatomizer can be used. Such formulations can be in the form of a finepowder for pulmonary administration from a powder inhalation device orself-propelling powder-dispensing formulations. In the case ofself-propelling solution and spray formulations, the effect may beachieved either by choice of a valve having the desired spraycharacteristics (i.e., being capable of producing a spray having thedesired particle size) or by incorporating the active ingredient as asuspended powder in controlled particle size. For administration byinhalation, the compounds also can be delivered in the form of anaerosol spray from pressured container or dispenser which contains asuitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration also can be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants generally are known in the art, and include, forexample, for transmucosal administration, detergents and bile salts.Transmucosal administration can be accomplished through the use of nasalsprays or suppositories. For transdermal administration, the activecompounds typically are formulated into ointments, salves, gels, orcreams as generally known in the art.

The active compounds may be prepared with carriers that will protect thecompound against rapid elimination from the body, such as a controlledrelease formulation, including implants and microencapsulated deliverysystems. Biodegradable, biocompatible polymers can be used, such asethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Methods for preparation of suchformulations will be apparent to those skilled in the art. Liposomalsuspensions can also be used as pharmaceutically acceptable carriers.These can be prepared according to methods known to those skilled in theart, for example, as described in U.S. Pat. No. 4,522,811.

Oral or parenteral compositions can be formulated in dosage unit formfor ease of administration and uniformity of dosage. Dosage unit formrefers to physically discrete units suited as unitary dosages for thesubject to be treated; each unit containing a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on the unique characteristics of the active compound and theparticular therapeutic effect to be achieved, and the limitationsinherent in the art of compounding such an active compound for thetreatment of individuals. Furthermore, administration can be by periodicinjections of a bolus, or can be made more continuous by intravenous,intramuscular or intraperitoneal administration from an externalreservoir (e.g., an intrvenous bag).

Where adhesion to a tissue surface is desired the composition caninclude the drug dispersed in a fibrinogen-thrombin composition or otherbioadhesive. The compound then can be painted, sprayed or otherwiseapplied to the desired tissue surface. Alternatively, the drugs can beformulated for parenteral or oral administration to humans or othermammals, for example, in therapeutically effective amounts, e.g.,amounts which provide appropriate concentrations of the drug to targettissue for a time sufficient to induce the desired effect.

Where the active compound is to be used as part of a transplantprocedure, it can be provided to the living tissue or organ to betransplanted prior to removal of tissue or organ from the donor. Thecompound can be provided to the donor host. Alternatively or, inaddition, once removed from the donor, the organ or living tissue can beplaced in a preservation solution containing the active compound. In allcases, the active compound can be administered directly to the desiredtissue, as by injection to the tissue, or it can be providedsystemically, either by oral or parenteral administration, using any ofthe methods and formulations described herein and/or known in the art.Where the drug comprises part of a tissue or organ preservationsolution, any commercially available preservation solution can be usedto advantage. For example, useful solutions known in the art includeCollins solution, Wisconsin solution, Belzer solution, Eurocollinssolution and lactated Ringer's solution.

The active compound may be administered directly to a tissue locus byapplying the compound to a medical device that is placed in contact withthe tissue. For example, an active compound may be applied to a stent atthe site of vascular injury. Stents can be prepared by any of themethods well known in the pharmaceutical art. See, e.g., Fattori, R. andPiva, T., “Drug-Eluting Stents in Vascular Intervention,” Lancet, 2003,361, 247–249; Morice, M. C., “A New Era in the Treatment of CoronaryDisease?” European Heart Journal, 2003, 24, 209–211; and Toutouzas, K.et al., “Sirolimus-Eluting Stents: A Review of Experimental and ClinicalFindings,” Z. Kardiol., 2002, 91(3), 49–57. The stent may be fabricatedfrom stainless steel or another bio-compatible metal, or it may be madeof a bio-compatible polymer. The active compound may be linked to thestent surface, embedded and released from polymer materials coated onthe stent, or surrounded by and released through a carrier which coatsor spans the stent. The stent may be used to administer single ormultiple active compounds to tissues adjacent to the stent.

Active compound as identified or designed by the methods describedherein can be administered to individuals to treat disorders(prophylactically or therapeutically). In conjunction with suchtreatment, pharmacogenomics (i.e., the study of the relationship betweenan individual's genotype and that individual's response to a foreigncompound or drug) may be considered. Differences in metabolism oftherapeutics can lead to severe toxicity or therapeutic failure byaltering the relation between dose and blood concentration of thepharmacologically active drug. Thus, a physician or clinician mayconsider applying knowledge obtained in relevant pharmacogenomicsstudies in determining whether to administer a drug as well as tailoringthe dosage and/or therapeutic regimen of treatment with the drug.

In therapeutic use for treating, or combating, bacterial infections inmammals, the compounds or pharmaceutical compositions thereof will beadministered orally, parenterally and/or topically at a dosage to obtainand maintain a concentration, that is, an amount, or blood-level ortissue level of active component in the animal undergoing treatmentwhich will be anti-microbially effective. The term “effective amount” isunderstood to mean that the compound of the invention is present in oron the recipient in an amount sufficient to elicit biological activity,for example, anti-microbial activity, anti-fungal activity, anti-viralactivity, anti-parasitic activity, anti-proliferative activity,anti-inflammatory activity or ameliorating a symptom of agastrointestinal motility disorder. Generally, an effective amount ofdosage of active component will be in the range of from about 0.1 toabout 100, more preferably from about 1.0 to about 50 mg/kg of bodyweight/day. The amount administered will also likely depend on suchvariables as the type and extent of disease or indication to be treated,the overall health status of the particular patient, the relativebiological efficacy of the compound delivered, the formulation of thedrug, the presence and types of excipients in the formulation, and theroute of administration. Also, it is to be understood that the initialdosage administered may be increased beyond the above upper level inorder to rapidly achieve the desired blood-level or tissue level, or theinitial dosage may be smaller than the optimum and the daily dosage maybe progressively increase during the course of treatment depending onthe particular situation. If desired, the daily dose may also be dividedinto multiple doses for administration, for example, 2–4 four times perday.

In light of the foregoing, the specific examples presented below areillustrative only and are not intended to limit the scope of theinvention. Other generic and specific configurations will be apparent tothose persons skilled in the art.

6. EXAMPLES

Some of the abbreviations used in the following experimental details ofthe synthesis of the examples are defined below:

hr = hour(s) min = minute(s) mol = mole(s) mmol = millimole(s) M = molarμM = micromolar g = gram(s) μg = microgram(s) rt = room temperature L =liter(s) mL = milliliter(s) Et₂O = diethyl ether THF = tetrahydrofuranDMSO = dimethyl sulfoxide EtOAc = ethyl acetate Et₃N = triethylaminei-Pr₂NEt = diisopropylethylamine CH₂Cl₂ = methylene chloride CHCl₃ =chloroform CDCl₃ = deuterated chloroform CCl₄ = carbon tetrachlorideMeOH = methanol CD₃OD = deuterated methanol EtOH = ethanol DMF =dimethylformamide BOC = t-butoxycarbonyl CBZ = benzyloxycarbonyl TBS =t-butyldimethylsilyl TBSCl = t-butyldimethylsilyl chloride TFA =trifluoroacetic acid DBU = diazabicycloundecene TBDPSCl =t-butyldiphenylchlorosilane Hunig's Base = N,N-diisopropylethylamineDMAP = 4-dimethylaminopyridine CuI = copper (I) iodide MsCl =methanesulfonyl chloride NaN₃ = sodium azide Na₂SO₄ = sodium sulfateNaHCO₃ = sodium bicarbonate NaOH = sodium hydroxide MgSO₄ = magnesiumsulfate K₂CO₃ = potassium carbonate KOH = potassium hydroxide NH₄OH =ammonium hydroxide NH₄Cl = ammonium chloride SiO₂ = silica Pd—C =palladium on carbon Pd(dppf)Cl₂ =dichloro[1,1′-bis(diphenylphosphino)ferrocene] palladium (II)

Nuclear magnetic resonance (NMR) spectra were obtained on a BrukerAvance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300spectrometer. Common reaction solvents were either high performanceliquid chromatography (HPLC) grade or American Chemical Society (ACS)grade, and anhydrous as obtained from the manufacturer unless otherwisenoted. “Chromatography” or “purified by silica gel” refers to flashcolumn chromatography using silica gel (EM Merck, Silica Gel 60, 230–400mesh) unless otherwise noted.

Example 1 Exemplary Oxazolidinone Derivatives

Exemplary compounds synthesized in accordance with the invention arelisted in Table 2.

TABLE 2 Compound Number Structure 142

143

144

145

146

147

148

149

150

151

152

153

175

176

177

178

179

180

181

182

183

184

185

186

187

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

Example 2 Synthesis of Compounds 142 and 143

Scheme 28 below depicts the synthesis of compounds 142 and 143 using thechemistries previously exemplified. Briefly, 2-methylamino-ethanol wasalkylated with propargyl bromide 154 and tosylate 155 to produce alkynes156 and 157, respectively. Alkynes 156 and 157 were heated in thepresence of the azide intermediate 158 (Brickner, S. J. et al. (1996) J.MED. CHEM 39: 673) to produce compounds 142 and 143, respectively.

Synthesis of Tosylate 155

3-Butyn-1-ol (1.8 g, 25 mmol) was dissolved in methylene chloride(CH₂Cl₂) (40 mL) and triethylamine (Et₃N) (4.18 mL, 30 mmol). Thesolution was stirred at 0° C. followed by addition of p-toluenesulfonylchloride (5.05 g, 26.25 mmol). The reaction was allowed to warm to roomtemperature over a period of 1 hour and stirring was continuedovernight. Thin layer chromatography (TLC) analysis (hexanes/ethylacetate (EtOAc) 6:1) after 20 hours of reaction showed a completeconsumption of 3-butyn-1-ol. The precipitated triethylaminehydrochloride was filtered off and the filtrate washed with water (H₂O)(30 mL) and brine (30 mL). The organic layer was dried over sodiumsulfate (Na₂SO₄) and the solvent evaporated away to give 155 as alight-yellow oil (5.45 g, 97%). The crude oil was used without furtherpurification; however, it could be purified on a silica gel column,first eluting with 8% EtOAc in hexanes followed by 40% EtOAc in hexanes.

Synthesis of Alkyne 157

A suspension of O-tosyl-3-butyn-1-ol (2.8 g, 12.5 mmol),2-methylaminoethanol (0.93 mL, 11.4 mmol) and sodium bicarbonate(NaHCO₃) was heated at 50° C. for 20 hours. NaHCO₃ was filtered, thesolvent was evaporated, and the resulting residue was partitionedbetween H₂O (30 mL) and EtOAc (30 mL). The layers were separated and theaqueous layer was back extracted with EtOAc (4×20 mL). The combinedorganic layer was dried over Na₂SO₄ and the solvent evaporated away togive an oily residue. The oily crude was purified on silica gel columneluting with 5:1 CH₂Cl₂/methanol (MeOH) to give compound 157 as an oil(0.54 g, 37%).

Synthesis of Alkyne 156

Alkyne 156 was made from 2-methylaminoethanol and propargyl bromide asdescribed for alkyne 157 above.

Synthesis of Triazole 142

Azide 158 (0.15 g, 0.47 mmol) and alkyne 156 (0.212 g, 1.5 mmol) weredissolved in anhydrous tetrahydrofuran (THF) (10 mL) and Hunig's base (2mL, 11.6 mmol). To this solution was added copper iodide (CuI) (0.136 g,0.7 mmol) and the resulting suspension stirred at room temperature for16 hours TLC (chloroform (CHCl₃)/MeOH 10:1) showed a quantitativeconsumption of azide 158. Methylene chloride (30 mL) was added, thesuspension was filtered and solvent was evaporated from the filtrate.The residue was purified on silica gel eluting with 6–13% MeOH in CH₂Cl₂to provide triazole 142 (0.11 g, 50.6%). Data for 142: ¹H-NMR (50 MHz,CDCl₃) δ 7.78 (s, 1H), 7.30 (dd, J=15, 3 Hz, 1H), 6.98 (dd, J=9, 2 Hz,1H), 6.88 (t, J=10 Hz, 1H), 5.08 (m, 1H), 4.77 (m, 2H), 4.15 (t, J=10Hz, 1H), 3.94 (m, 1H), 3.85 (t, J=5 Hz, 4H), 3.76 (bs, 2H), 3.60 (m,2H), 3.03 (t, J=4 Hz, 4H), 2.53 (m, 2H), 2.26 (s, 3H).

Synthesis of Triazole 143

Azide 158 (0.383 g, 1.2 mmol) and alkyne 157 (0.24 g, 1.9 mmol) weredissolved in anhydrous THF (12 mL) and Hunig's base (3 mL, 17.4 mmol).To this solution was added CuI (0.43 g, 2.2 mmol) and the resultingsuspension was stirred at room temperature for 3 hours. TLC (CH₂Cl₂/MeOH9:1) showed that the reaction was complete within 3 hours with nofurther consumption of azide 158 upon stirring overnight. Methylenechloride (50 mL) was added, the suspension was filtered and solvent wasevaporated from the filtrate. The residue was purified on silica geleluting with 10–20% MeOH in CH₂Cl₂ to provide triazole 143 (0.108 g,20%). Data for 143: ¹H-NMR (500 MHz, CDCl₃/CD₃OD) δ 7.78 (s, 1H), 7.33(dd, J=15, 3 Hz, 1H), 7.02 (dd, J=9, 2 Hz, 1H), 6.95 (t, J=9 Hz, 1H),5.10 (m, 1H), 4.76 (m, 2H), 4.19 (t, J=9 Hz, 1H), 3.93 (m, 1H), 3.87 (t,J=5 Hz, 4H), 3.65 (m, 2H), 3.06 (t, J=5 Hz, 4H), 2.90 (t, J=4 Hz, 2H),2.75 (t, J=5 Hz, 2H), 2.62 (t, J=6 Hz, 2H), 2.34 (s, 3H).

Example 3 Synthesis of Compound 144

Scheme 29 below depicts the synthesis of compound 144 using thechemistries previously exemplified. Cycloaddition of azide 158 andalkyne 159 produced triazole 160. Tosylation of the alcohol of triazole160, followed by alkylation with 2-methylamino-ethanol, produced4-substituted triazole 144.

Synthesis of Alcohol 160

Azide 158 (0.15 g, 0.47 mmol) and 4-pentyn-1-ol (0.034 g, 0.39 mmol)were dissolved in anhydrous THF (10 mL) and Hunig's base (2 mL, 11.6mmol). To this solution was added CuI (0.136 g, 0.7 mmol) and theresulting suspension was stirred at room temperature for 16 hours. TLC(CHCl₃/MeOH 10:1) showed a quantitative consumption of azide 158.Methylene chloride (30 mL) was added, the suspension was filtered andsolvent was evaporated from the filtrate. The residue was purified onsilica gel eluting with 5–7% MeOH in CH₂Cl₂ to provide 160 (0.077 g,48.7%).

Synthesis of Triazole 144

Compound 160 (0.072 g, 0.178 mmol) was dissolved in CH₂Cl₂ (2 mL) andEt₃N (0.09 mL, 0.63 mmol). To this solution was added p-toluenesulfonylchloride (0.0366 g, 0.19 mmol) and stirring continued at roomtemperature for 20 hours during which a quantitative consumption ofcompound 160 was noticed by TLC (CH₂Cl₂/MeOH 9:1). The reaction wasquenched with 10:1 H₂O/THF within 30 minutes and then partitionedbetween 10% NaHCO₃ (20 mL) and CH₂Cl₂ (20 mL). The two layers wereseparated; and the organic layer washed with saturated brine (3×15 mL)and dried over Na₂SO₄. Solvent was evaporated to give an oily residue.

The crude product above was dissolved in THF (3 mL) and Hunig's base(0.31 mL, 1.8 mmol). To this solution was added 2-(methylamino)ethanol(0.037 mL, 0.45 mmol) and stirring was continued at room temperature for20 hours. The reaction was partitioned between 5% MeOH in CH₂Cl₂ (30 mL)and saturated brine (20 mL). The two layers were separated and theresulting organic layer was washed with saturated brine (2×20 mL), driedover Na₂SO₄ and the solvent was evaporated. The crude product waspurified on silica gel eluting with 15–35% MeOH in CH₂Cl₂ toCH₂Cl₂/MeOH/ammonium hydroxide (NH₄OH) 3:1:0.05 to provide compound 144(0.041 g, 50%). Data for 144: ¹H-NMR (500 MHz, CDCl₃/CD₃OD) δ 7.77 (s,1H), 7.34 (dd, J=15, 3 Hz, 1H), 7.04 (dd, J=9, 2.5 Hz, 1H), 6.98 (t, J=9Hz, 1H), 5.12 (m, 1H), 4.77 (m, 2H), 4.20 (t, J=9 Hz, 1H), 3.96 (m, 1H),3.86 (t, J=5 Hz, 4H), 3.63 (m, 2H), 3.05 (t, J=5 Hz, 4H), 2.71 (t, J=6Hz, 2H), 2.52 (t, J=6 Hz, 2H), 2.42 (t, J=8 Hz, 2H), 2.26 (s, 3H), 1.83(m, 2H).

Example 4 Synthesis of Compounds 145–147

Scheme 30 below depicts the synthesis of compounds 145–147 usingchemistries previously exemplified. Des-methyl erythromycin amine 39 wasalkylated with propargyl bromide 154 or the tosylates 155 and 161 toproduce alkynes 162, 163 and 164, respectively. Hydrolysis of alkynes162, 163 and 164 produces alkynes 165, 166 and 167, respectively, whichwere then used in a cycloaddition reaction with azide 158 to produce the4-substituted triazole compounds 145, 146 and 147, respectively.

Synthesis of Tosylate 161

Tosylate 161 was made from 4-pentyn-1-ol using the same protocoldescribed for the synthesis of tosylate 155 above.

Synthesis of Alkyne 165

Alkyne 162 (800 mg) was stirred with 6N hydrochloric acid (HCl)overnight at ambient temperature and heated to 100° C. for 2 hours. Thedark solution was cooled to room temperature and extracted with CH₂Cl₂(3×8 mL) and ethyl ether (Et₂O) (3×8 mL). The aqueous phase wasconcentrated to obtain a foamy solid, which was redissolved in water (8mL) and neutralized with NaHCO₃. The solution was extracted with EtOAc(3×10 mL), dried with Na₂SO₄, concentrated and purified by flashchromatography (silica gel, 5% MeOH—CHCl₃) to give the alkyne 165 (85mg, 40%) as a mixture of anomers.

Synthesis of Alkyne 166 and 167

The same procedure used for the synthesis of alkyne 165 from 162 wasused to synthesize alkyne 166 from 163, and alkyne 167 from 164. Thealkynes 166 and 167 were used in subsequent chemistry without furtherpurification.

Synthesis of Triazole 145

To a solution of alkyne 165 (80 mg, 0.0402 mmol), azide 158 (155 mg,0.482 mmol), and Hunig's base (2.1 mL, 12.06 mmol) in THF (5 mL) wasadded CuI (156 mg, 0.804 mmol) and the mixture was stirred overnight atambient temperature. The reaction mixture was diluted with 10%MeOH—CHCl₃ (50 mL), washed with brine (2×50 mL), dried with Na₂SO₄, andconcentrated under reduced pressure. The crude mixture was purified byflash chromatography (silica gel, 10% MeOH—CHCl₃) to give compound 145(80 mg, 40%). Data for 145: ¹H-NMR (500 MHz, CDCl₃; partial structure) δ7.72 (s, 1H), 7.28 (d, 1H), 6.95–6.84 (m, 2H, m).

Synthesis of Triazoles 146 and 147

The same procedure used for the synthesis of triazole 145 from 165 wasused to synthesize triazole 146 from alkyne 166, and triazole 147 fromalkyne 167.

Example 5 Synthesis of Compounds 148–150

Scheme 31 below depicts the synthesis of compounds 148–150 using oneexemplary method. Alkynes 162, 163 and 164 were reacted with azide 158to produce a mixture of the 4-substituted triazoles 148, 149, and 150,respectively.

Scheme 32 below depicts the synthesis of compounds 149 and 150 using analternative exemplary method. Azide 158 was reacted with tosylates 155and 161 to produce triazole tosylates 168 and 169, respectively. Thereaction of compounds 168 and 169 with amine 39 produced compounds 149and 150, respectively.

Synthesis of Amine 39

Compound 39 was made from erythromycin A employing the proceduredescribed in U.S. Pat. No. 3,725,385.

Synthesis of Alkyne 163

A mixture of des(N-methyl)erythromycin 39 (1.0 g, 1.4 mmol) and tosylate155 (1.25 g, 5.6 mmol) in anhydrous THF (15 mL) and Hunig's base (2.2mL, 11.9 mmol) was kept stirring at 55° C. for 48 hours. The reactionwas poured into CH₂Cl₂ (50 mL), extracted with 2% aqueous NH₄OH (3×30mL) and saturated brine (1×30 mL). The organic layer was dried overNa₂SO₄ and the solvent was evaporated away. The crude was purified onsilica gel column eluting with CH₂Cl₂/MeOH 10:1 to give 163 (0.35 g,32%).

Synthesis of Alkyne 164

Alkyne 164 was made from des(N-methyl)erythromycin 39 and tosylate 161using the same procedure described for alkyne 163.

Synthesis of Alkyne 162

Alkyne 162 was made from des(N-methyl)erythromycin 39 and propargylbromide using the same procedure described for alkyne 163.

Synthesis of Tosylate 168

Azide 158 (1.5 g, 4.7 mmol) and tosylate 155 (0.875 g, 3.9 mmol) weredissolved in anhydrous THF (25 mL) and Hunig's base (10 mL, 57.4 mmol).To this solution was added CuI (1.36 g, 7.0 mmol) and the resultingsuspension was stirred at room temperature for 2 hours. TLC (CHCl₃/MeOH10:1) showed a quantitative consumption of azide 158. The reaction waspoured into CH₂Cl₂ (60 mL), extracted with saturated NaHCO₃ (3×30 mL)and saturated brine (2×30 mL). The organic layer was dried over Na₂SO₄and the solvent was evaporated away. The crude was purified on silicagel column eluting with 0–3% MeOH in CH₂Cl₂ to give 168 (1.34 g, 63%).

Synthesis of Triazole 149

Method A: Alkyne 163 (0.80 g, 1.036 mmol) and azide 158 (0.50 g, 1.6mmol) were dissolved in anhydrous THF (10 mL) and Hunig's base (2.2 mL,11.6 mmol). To this solution was added CuI (0.403 g, 2.07 mmol) and theresulting suspension stirred at room temperature for 2 hours. CH₂Cl₂ (60mL) was added, the solution wad extracted with saturated NaHCO₃ (3×30mL), NH₄Cl (3×30 mL) and saturated brine (30 mL). The organic layer wasdried over Na₂SO₄ and the solvent was evaporated. The crude was purifiedon silica gel eluting with CH₂Cl₂/MeOH 15:1 to 10:1 to provide triazole149 (0.91 g, 80%).

Method B: A mixture of des(N-methyl)erythromycin 39 (0.25 g, 0.342 mmol)and tosylate 168 (0.28 g, 0.51 mmol) in anhydrous THF (5 mL) and Hunig'sbase (0.65 mL, 3.51 mmol) was stirred at 55° C. for 48 hours. Thereaction was poured into CH₂Cl₂ (30 mL), extracted with saturated NaHCO₃(3×20 mL) and saturated brine (1×20 mL). The organic layer was driedover Na₂SO₄ and the solvent evaporated. The crude product was purifiedon silica gel column eluting with CH₂Cl₂/MeOH 15:1 to 10:1 to givetriazole 149 (0.151 g, 40%). Data for 149: ¹H-NMR, partial, (500 MHz,CDCl₃) δ 7.60 (s, 1H), 7.29 (dd, J=14, 3 Hz, 1H), 6.95 (dd, J=10, 3 Hz,1H), 6.86 (t, J=9 Hz, 1H), 5.00 (m, 2H), 4.85 (d, J=5 H, 1H), 4.67 (m,2H), 4.37 (d, J=7 Hz, 1H), 4.08 (t, J=10 Hz, 1H), 3.52 (d, J=8 Hz, 1H),3.44 (m, 1H), 2.66 (m, 2H), 0.82 (t, J=8 Hz, 3H).

Synthesis of Triazole 148

Triazole 148 was made from alkyne 162 and azide 158 using method A asdescribed for triazole 149.

Synthesis of Triazole 150

Triazole 150 was made from alkyne 164 and azide 158 using both methods Aand B described for triazole 149. Data for 150: ¹H-NMR, partial, (500MHz, CDCl₃) δ 7.49 (s, 1H), 7.26 (dd, J=15, 3 Hz, 1H), 6.91 (dd, J=10, 3Hz, 1H), 6.84 (t, J=9 Hz, 1H), 5.00 (m, 2H), 4.85 (d, J=5 H, 1H), 4.67(m, 2H), 4.38 (d, J=8 Hz, 1H), 4.07 (t, J=10 Hz, 1H), 3.52 (d, J=8 Hz,1H), 3.44 (m, 1H), 2.69 (m, 2H), 0.78 (t, J=8 Hz, 3H).

Example 6 Synthesis of Compounds 151–153

Scheme 33 below depicts the synthesis of compounds 151–153 using thechemistries previously exemplified. Demethylation of azithromycin 170selectively produced amine 171. Amine 171 was alkylated bromide 154 andtosylates 155 and 161 to produce alkynes 172, 173 and 174, respectively.Cycloaddition of alkynes 172, 173 and 174 with azide 158 producedcompounds 151, 152 and 153, respectively.

Synthesis of des(N-methyl)azithromycin 171

Azithromycin 170 (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712g, 8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solutionwas kept at 50° C. followed by addition of iodine (I₂) (0.272 g, 1.07mmol) in three batches within 3 minutes. The reaction was maintained ata pH between 8–9 by adding 1N sodium hydroxide (NaOH) (1 mL) at 10 minand 45 minute intervals. The solution turned colorless within 45minutes, however, stirring was continued for 2 hours. TLC(CH₂Cl₂/MeOH/NH₄OH 10:1:0.05) after 2 hours showed a single majorproduct (Rf=0.66). The reaction was cooled to room temperature, pouredinto H₂O (75 mL) containing NH₄OH (1.5 mL) and extracted with CHCl₃(3×30 mL). The combined organic layer was washed with H₂O (30 mL)containing NH₄OH (1.5 mL), dried over Na₂SO₄ and the solvent evaporatedto give a white residue. The crude was purified on silica gel columneluting with CH₂Cl₂/MeOH/NH₄OH 18:1:0.05 to 10:1:0.05 to provide amine171 (0.41 g, 55%).

Synthesis of Alkyne 172

Alkyne 172 was made from des(N-methyl)azithromycin 171 and propargylbromide using the same procedure described for the synthesis of compound163.

Synthesis of Alkyne 173

Alkyne 173 was made from des (N-methyl)azithromycin 171 and tosylate 155using the same procedure described for the synthesis of compound 163.

Synthesis of Triazole 151

Triazole 151 was made from alkyne 172 and azide 158 using method A asdescribed for the synthesis of compound 149.

Synthesis of Triazole 152

Triazole 152 was made from alkyne 173 and azide 158 using method A asdescribed for the synthesis of compound 149. Data for 152: ¹H-NMR (300MHz, CDCl₃, partial); δ 7.63 (s, 1H), 7.34 (dd, J=14, 2 Hz, 1H), 6.98(dd, J=9, 2 Hz, 1H), 6.90 (t, J=9 Hz, 1H), 5.11 (d, J=4 Hz, 1H), 4.96(m, 1H), 4.71 (m, 3H), 4.44 (d, J=7 Hz, 1H), 4.30 (d, J=2 Hz, 1H), 4.10(m, 2H), 3.86 (m, 5H), 3.04 (m, 5H), 0.90 (t, J=7 Hz, 3H).

Synthesis of Triazole 153

Triazole 153 was made from alkyne 174 and azide 158 using method A asdescribed for compound 149. Data for 153: ¹H-NMR, partial, (500 MHz,CDCl₃) δ 7.50 (s, 1H), 7.29 (dd, J=15, 3 Hz, 1H), 6.94 (dd, J=10, 3 Hz,1H), 6.87 (t, J=9 Hz, 1H), 5.13 (m, 1H), 5.00 (m, 1H), 4.71 (m, 2H),4.43 (d, J=7 Hz, 1H), 4.26 (bs, 1H), 3.61 (d, J=8 Hz, 1H), 0.78 (t, J=8Hz, 3H).

Synthesis of Alkyne 174

Alkyne 174 was made from des(N-methyl)azithromycin 171 and tosylate 161using the same procedure described for compound 163.

Example 7 Synthesis of Compound 175

Triazole 152 was hydrolyzed with dilute acid to afford the des-cladinosederivative 175.

Synthesis of Triazole 175

Compound 152 (0.120 g, 0.108 mmol) was dissolved in 0.25N HCl (10 mL)and the solution was kept stirring at room temperature for 24 h. Thereaction was extracted with CH₂Cl₂ (2×20 mL) and the organic layer wasdiscarded. The aqueous layer was basified with conc. NH₄OH and thenextracted with CH₂Cl₂ (3×30 mL). The combined organic layer wasextracted with saturated brine (1×20 mL), and dried over Na₂SO₄. TLC(CH₂Cl₂/MeOH/NH₄OH 10:1:0.05) showed>95% conversion to a new lower Rfproduct (Rf=0.56). The solvent was evaporated to provide 175 as a whitesolid (0.101 g, 98%). Data for 175: ¹H-NMR (300 MHz, CDCl₃, partial): δ7.58 (s, 1H), 7.26 (dd, J=14, 2 Hz, 1H), 6.91 (dd, J=10, 2 Hz, 1H), 6.83(t, J=9 Hz, 1H), 4.97 (m, 1H), 4.63–4.66 (m, 3H), 4.36 (d, J=7 Hz, 1H),4.02 (bs, 1H), 3.78 (t, J=4 Hz, 4H), 2.96 (t, J=5 Hz, 4H), 0.83 (t, J=7Hz, 3H).

Example 8 Synthesis of Compounds 176–178

Scheme 34 below depicts the synthesis of compounds 176–178 using thechemistries previously exemplified. Azide 188 was treated with alkyne163 to afford triazole 176. The same azide was used to make triazoles177 and 178 from alkynes 164 and 173 respectively.

Synthesis of Azide 188

The known azide 188 can be synthesized following the procedure reportedin the literature (Gregory, W. A. et al. J. Med. Chem. 1989, 32, 1673).

Synthesis of Triazole 176

This compound was made from alkyne 163 and azide 188 using method A asdescribed for compound 149. Data for 176: ¹H-NMR (300 MHz, CDCl₃,partial): δ 7.90 (d, J=9 Hz, 2H), 7.59 (s, 1H), 7.50 (d, J=9 Hz, 2H),5.01–5.15 (m, 2H), 4.84 (d, J=4 Hz, 1H), 4.71 (m, 2H), 4.36 (d, J=7 Hz,1H), 4.20 (t, J=7 Hz, 1H) 3.93–4.02 (m, 4H), 3.79 (bs, 1H), 0.79 (t, J=7Hz, 3H).

Synthesis of Triazole 177

This compound was made from alkyne 164 and azide 188 using method A asdescribed for compound 149. Data for 177: ¹H-NMR (300 MHz, CDCl₃,partial): δ 7.98 (d, J=9 Hz, 2H), 7.53–7.56 (m, 3H), 5.07–5.19 (m, 2H),4.89 (d, J=4 Hz, 1H), 4.75 (m, 2H), 4.43 (d, J=7 Hz, 1H), 4.22 (t, J=7Hz, 1H), 4.01 (m, 1H), 3.92 (s, 1H), 3.83 (s, 1H), 0.86 (t, J=7 Hz, 3H).

Synthesis of Triazole 178

This compound was made from alkyne 173 and azide 188 using method A asdescribed for compound 149. Data for 178: ¹H-NMR (300 MHz, CDCl₃,partial): δ 7.90 (d, J=9 Hz, 2H), 7.55 (s, 1H), 7.48 (d, J=8 Hz, 2H),4.97–5.02 (m, 2H), 4.61–4.67 (m, 3H), 4.36 (d, J=7 Hz, 1H), 3.95–4.21(m, 5H), 3.58 (m, 2H), 3.36 (m, 1H), 3.14–3,25 (m, 5H), 0.82 (t, J=7 Hz,3H).

Example 9 Synthesis of Compounds 179–180

Scheme 35 below depicts the synthesis of compounds 179 and 180 using thechemistries previously exemplified. Azide 189 was treated with alkyne163 to afford triazole 179. The same azide was used to make triazole 180from alkyne 173.

Synthesis of Azide 189

The azide was synthesized from 3-fluoroaniline using the chemistryreported in the literature (Brickner, S. J. et al. J. Med. Chem. 1996,39, 673).

Synthesis of Triazole 179

This compound was made from alkyne 163 and azide 189 using method A asdescribed for compound 149. Data for 179: ¹H-NMR (300 MHz, CDCl₃,partial): δ 7.55 (s, 1H), 7.28–7.36 (m, 1H), 7.09 (dd, J=8 Hz, 1.6 Hz,1H), 6.83 (m, 1H), 5.04–5.12 (m, 2H), 4.88 (d, J=5 Hz, 1H), 4.72 (m,2H), 4.39 (d, J=7 Hz, 1H), 4.16 (t, J=7 Hz, 1H), 3.82 (s, 1H), 0.83 (t,J=7 Hz, 3H).

Synthesis of Triazole 180

This compound was made from alkyne 173 and azide 189 using method A asdescribed for compound 149. Data for 180: ¹H-NMR (300 MHz, CDCl₃,partial): δ 7.55 (s, 1H), 7.22–7.29 (m, 1H), 7.02 (d, J=8 Hz, 1H), 6.77(m, 1H), 5.01 (m, 2H), 4.63–4.66 (m, 3H), 4.21–4.37 (m, 3H), 3.86 (m,1H), 3.60 (m, 2H), 3.41 (m, 1H), 0.82 (t, J=8 Hz, 3H).

Example 10 Synthesis of Compound 181

Scheme 36 below depicts the synthesis of compound 181 from azide 194 andalkyne 163. The synthesis of azide 194 began with the conversion oftert-butylamine to benzylcarbamate 190. Carbamate 190 was treated withn-butyllithium and R-glycidyl butyrate to afford alcohol 191. Mesylationto give 192 was followed by cleavage of the t-butyl group withtrifluoroacetic acid to provide mesylate 193. Displacement of themesylate with sodium azide yielded azide 194. The azide was treated withalkyne 163 to afford triazole 181.

Synthesis of Carbamate 190

Sodium bicarbonate (34.48 g., 410.4 mmol) was dissolved in water (680mL) and tert-butylamine (29 mL, 273.6 mmol) was added. The mixture wascooled to 0° C., and benzyl chloroformate (37 mL) was added. The mixturewas stirred 5 min at 0° C., the cold bath removed, and then stirring wascontinued at room temperature overnight (˜16 hours). The mixture wasevaporated, and partitioned with a 1:1 mixture of ethyl acetate andwater. The organic layer was washed with water, 1N HCl, and then brine.The organic layer was dried with Na₂SO₄, and evaporated to yield 190(48.45 g., 85% yield) of suitable purity for use in subsequentreactions. Data for 190: ¹HNMR (300 MHz, CDCl₃): δ 7.37–7.26 (m, 5H),5.04 (s, 2H), 4.77 (brs, 1H), 1.31 (s, 9H).

Synthesis of Alcohol 191

Carbamate 190 (40 g., 193 mmol) was dissolved in 540 mL tetrahydrofuran,and the solution cooled to −78° C. n-Butyllithium (2.5M in hexane, 85mL, 212.4 mmol) was added slowly, and the mixture allowed to stir for 45min at −78° C. R-Glycidyl butyrate (32.6 mL, 212.4 mmol) was added, andthe mixture was stirred for 1 h at −78° C. The bath was removed and thereaction allowed to stir overnight at room temperature. The mixture hadbecome thick with solids, and an additional 150 mL of tetrahydrofuranwas added, and stirring was continued for another hour. The reaction wasquenched with 25 mL saturated ammonium chloride solution, andpartitioned with ethyl acetate and water. The aqueous layer wasextracted thrice with ethyl acetate, and the combined organic layer waswashed with brine, dried (Na₂SO₄), and evaporated to yield 191 (15.21g., 46% yield) of suitable purity for use in subsequent reactions. Datafor 191: ¹HNMR (300 MHz, CDCl ₃): δ 4.29 (dd, J=9, 2 Hz, 1H), 4.19 (dd(app), J=8, 8 Hz, 1H), 3.94–3.87 (m, 1H), 3.84–3.76 (m, 1H), 3.71–3.61(m, 1H), 2.50–2.42 (m, 1H), 1.44 (s, 9H).

Synthesis of Mesylate 192

Alcohol 191 (9.00 g., 52.0 mmol) was dissolved in 215 mL methylenechloride, and the mixture cooled to 0° C. Triethylamine (14.5 mL, 104mmol) was added, followed by methanesulfonyl chloride (4.43 mL, 57.2mmol). The mixture was allowed to warm to room temperature and stirredovernight. Methylene chloride (120 mL) was added, and the mixture washedtwice with 1N HCl, then twice with 10% aqueous sodium carbonate, andthen brine. The organic phase was dried (Na₂SO₄), and evaporated to halfits volume. Hexane was added, and the solvents evaporated to form awhite precipitate. Before the solution was allowed to evaporate todryness, more hexane was added and evaporation continued. Again, beforethe solution was allowed to evaporate to dryness, it was filtered andthe solid collected. The precipitate was dried to afford mesylate 192(11.16 g., 85% yield). Data for 192: ¹HNMR (300 MHz, CDCl₃): δ 4.39–4.34(m, 1H), 4.25–4.23 (m, 2H), 4.18–4.12 (m,2H), 3.10 (s, 3H), 1.47 (s,9H).

Synthesis of Mesylate 193

A solution of mesylate 192 (562 mg, 2.20 mmol) in trifluoroacetic acid(8.0 mL) was heated at 60° C. for 4 h. The reaction mixture was cooledto room temperature, and the solvent was evaporated. The remainingresidue was thrice dissolved in chloroform (50 mL) and evaporated toafford mesylate 193 (450 mg, 100% yield) as a tan solid. Data for 193:¹HNMR (300 MHz, DMSO): δ 7.86 (brs, 1H), 4.34–4.27 (m, 1H), 4.12–4.08(m, 2H), 4.05–3.98 (m, 2H), 3.14 (s, 3H).

Synthesis of Azide 194

A solution of mesylate 193 (400 mg, 2.10 mmol) in dimethylformamide (4.0mL) was treated with sodium azide (195 mg, 3.00 mmol) and the mixtureheated to 80° C. for 3 h. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate (100 mL), and washed with brine(2×50 mL). Drying (Na₂SO₄), and evaporation provided azide 194 (105 mg,35% yield) as a yellow oil of suitable purity for use in subsequentreactions. Data for 194: ¹HNMR (300 MHz, CDCl₃): δ 6.29 (s, 1H),4.45–4.40 (m, 1H), 4.13–4.07 (m, 1H), 3.97–3.78 (m, 1H), 3.48–3.35 (m,2H).

Synthesis of Triazole 181

A solution of alkyne 163 (135 mg, 0.180 mmol) in tetrahydrofuran (3.0mL) was treated with azide 194 (50 mg, 0.350 mmol), i-Pr₂NEt (1.00 mL,5.30 mmol) and copper (I) iodide (50 mg, 0.270 mmol), and the mixturewas stirred under argon at room temperature for 15 h. The reactionmixture was diluted with methylene chloride (100 mL), washed withsaturated aqueous NH₄Cl (50 mL), and brine (50 mL). The organic phasewas dried (Na₂SO₄), and evaporated. The residue was chromatographed onsilica gel using a 5–20% gradient of methanol in 1:1 ethylacetate/methylene chloride as eluant to provide 80 mg of crude product.The crude was dissolved in methylene chloride (100 mL) and washed withsaturated aqueous NH₄Cl (3×100 mL) and dried again. Preparative thinlayer chromatography (1:4.5:4.5 methanol/methylene chloride/ethylacetate as eluant) provided triazole 181 (9.0 mg, 6% yield) as a whitefilm. Data for 181: MS (ESI) m/z 914 (M+H)⁺. ¹HNMR (300 MHz, CDCl₃,partial): δ 7.54 (s, 1H), 6.12 (s, 1H), 5.01–4.95 (m, 1H), 4.79 (d, J=4Hz, 1H), 4.19–4.11 (m, 2H), 4.08–4.02 (m, 2H), 3.83 (s, 1H), 3.74 (s,1H)), 3.48–3.30 (m, 4H), 3.23 (s, 3H), 3.09–2.90 (m, 4H), 2.87–2.73 (m,4H), 2.70–2.50 (m, 2H), 2.28 (s, 3H), 0.80 (t (app), J=7 Hz, 3H).

Example 11 Synthesis of Compounds 182–184

Scheme 37 below depicts the synthesis of compounds 182–184 starting fromclarithromycin (195). Clarithromycin is demethylated to afford secondaryamine 196 which was subsequently alkylated with tosylate 155 to providealkyne 197. Alkyne 197 was treated with azides 158, 188, and 189 toyield triazoles 182, 183, and 184 respectively.

Synthesis of Amine 196

To a mixture of clarithromycin (195) (1.00 g, 1.3 mmol) and NaOAc.3H₂0(0.885 g, 6.5 mmol) was added MeOH—H₂O (20 mL, 4:1), and the mixtureheated to 55–60° C. Iodine (0.330 g, 1.3 mmol) was added portionwise andthe reaction stirred at 55–60° C. for 3 h. The reaction mixture waspoured into 50 mL CHCl₃ containing 1 mL ammonium hydroxide. It wasextracted with CHCl₃ (4×50 mL), washed with water (70 mL) containing 5mL ammonium hydroxide, dried (anhydrous Na₂SO₄), concentrated andpurified by flash chromatography (silica gel, CHCl₃:MeOH:NH₄OH100:10:0.1) to afford 196. Yield: 0.9 g (92%).

Synthesis of Alkyne 197

To a solution of N-desmethyl clarithromycin 196 (3.00 g, 4.08 mmol) andtosylate 155 (1.40 g, 6.13 mmol) in THF (45 mL) was added Hunig's base(15 mL) and the mixture was refluxed for 48 h. The reaction mixture wasconcentrated under reduced pressure and redissolved in CHCl₃ (100 mL).The organic layer was washed with brine (3×100 mL), dried (over Na₂SO₄),and concentrated under reduced pressure. After purification by flashchromatography (silica gel, 5% MeOH in CHCl₃), 2.50 g (78% yield) ofpure product 197 was obtained. Data for 197: ¹HNMR (300 MHz, CDCl₃,partial): δ 0.85 (t, 3H), 2.25 (s, 3H), 3.00 (s, 3H), 3.20 (s, 1H), 3.25(m, 1H), 3.30 (s, 3H), 3.50 (m, 1H), 3.55 (s, 1H), 3.65 (d, 1H), 3.75(m, 3H), 4.00 (s, 1H), 4.05 (m, 1H), 4.45 (d, 1H), 4.95 (d, 1H), 5.10(dd, 1H).

Synthesis of Triazole 182

To a solution of alkyne 197 (0.100 g, 0.127 mmol), azide 158 (0.082 g,0.254 mmol), and Hunig's Base (0.417 mL) in THF (1.5 mL) was added CuI(0.030 g, 0.16 mmol), and the reaction mixture was stirred at roomtemperature for 2 hours. The reaction mixture was diluted with CHCl₃ (50mL), washed with saturated NH₄Cl (3×50 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude reaction mixture waspurified on a silica gel column eluting with 3% 2M NH₃-MeOH in CH₂Cl₂ toafford 1, 4 triazole isomer 182 (0.125 g). Data for 182: ¹HNMR (300 MHz,CDCl₃, partial); δ 0.85 (t, 3H), 2.25 (s, 3H), 3.65 (d, 1H), 4.10 (t,1H), 4.40 (d, 1H), 4.70 (dd, 2H), 4.90 (d, 1H), 5.10–4.95 (m, 2H), 6.88(t, 1H), 7.00 (dt, 1H), 7.35 (dd, 1H), 7.60 (s, 1H).

Synthesis of Triazole 183

The same protocol used above to synthesize target 182 was used for thecycloaddition of alkyne 197 (0.100 g, 0.127 mmol) and azide 188 (0.066g, 0.254 mmol) to afford target 183. Data for 183: ¹HNMR (300 MHz,CDCl₃, partial): δ 0.85 (t, 3H), 2.20 (s, 3H), 2.55 (s, 3H), 3.00 (s,3H), 3.30 (s, 3H), 3.70 (d, 1H), 3.95–4.05 (m, 3H), 4.20 (t, 1H), 4.45(d, 1H), 4.70 (dd, 2H), 4.90 (d, 1H), 5.10–5.00 (m, 2H), 7.55 (d, 2H),7.60 (s, 1H), 7.95 (d, 2H).

Synthesis of Triazole 184

Cycloaddition of alkyne 197 (0.050 g, 0.0636 mmol) with azide 189 (0.030g, 0.127 mmol), using the same procedure for the synthesis of 182,afforded target 184 (0.0253 g). Data for 184: MS (ESI) m/z 1022.3(M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 0.86 (t, 1H), 2.25 (s, 3H),3.00 (s, 3H), 3.30 (s, 3H), 3.50 (m, 1H), 3.65 (s, 1H), 4.10 (t, 1H),4.40 (d, 1H), 4.70 (dd, 2H), 4.85 (d, 1H), 5.00 (m, 2H), 6.85 (bt, 1H),7.10 (bd, 1H), 7.35 (bt, 2H), 7.60 (s, 1H).

Example 12 Synthesis of Compound 185

Scheme 38 below depicts the synthesis of compound 185 starting fromalkyne 197. Alkyne 197 is hydrolyzed with dilute acid to afford thedes-cladinose derivative 198. The hydroxyl on the desosamine sugar of198 was acetylated to afford alcohol 199 which was then oxidized toketolide derivative 200. Deacylation of 200 provided alkyne 201, whichwas then treated with azide 158 to provide triazole 185.

Synthesis of Alcohol 198

To the alkyne 197 (0.700 g) was added 10 mL 0.9N HCl and the mixture wasstirred for 4 h at room temperature. The reaction mixture was saturatedwith sodium chloride and was adjusted to pH 8 using aqueous NH₄OHsolution. The solution was extracted with ethyl acetate (3×30 mL), dried(with Na₂SO₄), and concentrated under reduced pressure. Purification ofthe crude reaction mixture by flash chromatography (silica gel, 60%ethyl acetate in hexane) afforded 0.200 g (35% yield) of thedescladinose derivative 198. Data for 198: ¹HNMR (300 MHz, CDCl₃,partial): δ 0.82 (t, 3H), 2.25 (s, 3H), 3.00 (s, 3H), 3.25 (dd, 1H),3.55 (m, 2H), 3.70 (s, 1H), 3.85 (s, 1H), 3.95 (s, 1H), 4.40 (d, 1H),5.15 (dd, 1H).

Synthesis of Acetate 199

To a solution of 198 (0.200 g, 0.32 mmol) in acetone (2 mL) was addedacetic anhydride (0.050 mL, 0.5 mmol) and the mixture was stirredovernight at room temperature. The reaction was quenched with water andextracted with ethyl acetate (3×50 mL). The combined organic fractionswere washed with saturated sodium bicarbonate (3×50 mL), dried(anhydrous Na₂SO₄), and concentrated under reduced pressure. The crudereaction mixture was purified by flash chromatography (silica gel, 50%ethyl acetate in hexane) to yield 0.100 g (50% yield) of acetate 199.Data for 199: ¹HNMR(300 MHz, CDCl₃, partial): δ 0.84 (t, 3H), 2.00 (s,3H), 2.20 (s, 3H), 2.90 (s, 3H), 3.00 (q, 1H), 3.25 (s, 1H, 3.47 (m,2H), 3.70 (bs, 1H), 3.82 (bs, 1H), 3.97 (s, 1H), 4.60 (d, 1H), 4.77 (dd,1H), 5.15 (dd, 1H).

Synthesis of Ketolide 200

To a solution of acetate 199 (0.090 g, 0.134 mmol), EDC•-HCl (0.172 g,0.90 mmol), and DMSO (0.171 mL, 2.41 mmol) in CH₂Cl₂ (1.5 mL) was addeddropwise a solution of pyridinium trifluoroacetate (0.174 g, 0.90 mmol)in CH₂Cl₂ (1 mL) at 15° C. The reaction mixture was slowly warmed up toroom temperature and stirred for 3 h. The reaction was quenched withwater (2 mL), and allowed to stir for 30 min. The mixture was thenpoured into CHCl₃ (50 mL), and the organic layer was washed with water(2×50 mL), dried (over anhydrous Na₂SO₄), and concentrated under reducedpressure. The crude material was purified by flash chromatography(silica gel, 30% ethyl acetate in hexane) to yield 0.070 g (78%) of theketolide 200. Data for 200: MS (ESI) m/z 668 (M+H)⁺; ¹HNMR (300 MHz,CDCl₃, partial): δ 0.86 (t, 3H), 2.00 (s, 3H), 2.24 (s, 3H), 2.70 (s,3H), 2.95–3.10 (m, 1H), 3.15–3.05 (m, 1H), 3.45–3.65 (m, 1H), 3.80 (q,1H), 3.90 (s, 1H), 4.28 (d, 1H), 4.40 (d, 1H), 4.76 (dd, 1H), 5.10 (dd,1H).

Synthesis of Alkyne 201

A solution of ketolide 200 (0.230 g) in MeOH (10 mL) was heated at 50°C. for 48 h. The solvent was removed under reduced pressure to yieldpure deacetylated product 201 (0.190 g, 88%). Data for 201: MS (ESI) m/z626 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 0.85 (t, 3H), 2.25 (s,3H), 2.70 (s, 3H), 2.97 (q, 1H), 3.10 (t, 1H), 3.18 (dd, 1H), 3.5 (m,1H), 3.80–3.97 (m, 2H), 4.32 (m, 2H), 5.15 (dd, 1H).

Synthesis of Triazole 185

To a solution of 201 (0.050 g, 0.080 mmol), azide 158 (0.050 g, 0.16mmol), and Hunig's Base (0.417 mL) in THF (1.5 mL) was added CuI (0.030g, 0.16 mmol), and the reaction mixture was stirred at room temperaturefor 2 h. It was diluted with CHCl₃ (50 mL), washed with saturated NH₄Cl(3×50 mL), dried (anhydrous Na₂SO₄) and concentrated under reducedpressure. The crude reaction mixture was purified by flashchromatography (silica gel, 3% 2M NH₃-MeOH in CH₂Cl₂) to afford 185(0.043 g). Data for 185: MS (ESI) m/z 947.4 (M+H)⁺; ¹HNMR (300 MHz,CDCl₃, partial): δ 0.86 (t, 3H), 2.25 (s, 3H), 2.70 (s, 3H), 4.10 (t,1H), 4.30 (t, 2H), 4.70 (dd, 2H), 5.00 (m, 1H), 5.10 (dd, 1H), 6.90 (t,1H), 6.95 (dt, 1H), 7.25 (dd, 1H), 7.60 (s, 1H).

Example 13 Synthesis of Compounds 186 and 187

Scheme 39 below depicts the synthesis of compounds 186 and 187. Azide158 is treated 3-hydroxypropionitrile to yield tetrazole 186. Tetrazole186 was converted to tosylate 202 which then served to alkylate amine171 to afford tetrazole 187.

Synthesis of Tetrazole 186

A suspension of azide 158 (0.300 g, 0.940 mmol), 3-hydroxypropionitrile(1.0 mL, 14.2 mmol) and zinc bromide (ZnBr₂) (0.212 g, 0.940 mmol) in2-propanol/H₂O (4:1) was heated under reflux for 40 h. The reaction waspoured into CH₂Cl₂ (50 mL) and H₂O (20 mL) and carefully partitioned(caution: emulsion problem). The aqueous layer was back-extracted withCH₂Cl₂ (3×30 mL). The combined organic layer was dried over Na₂SO₄ andthe solvent was evaporated. The crude was purified on silica gel columneluting with 0–10% MeOH in CH₂Cl₂ to provide 186 (0.037 g, 10%). ¹H-NMR(300 MHz, CDCl₃, partial): δ 7.41 (dd, J=14, 3 Hz, 1H), 7.05–7.13 (m,2H), 6.93 (t, J=9 Hz, 1H), 4.78 (m, 1H), 3.65–4.04 (m, 10H), 3.04 (t,J=5 Hz, 4H), 2.48 (t, J=6 Hz, 2H).

Synthesis of Tosylate 202

Tetrazole 186 (0.028 g, 0.071 mmol) was dissolved in CH₂Cl₂ (2 mL) andEt₃N (0.015 mL, 0.107 mmol). To this solution was addedp-toluenesulfonyl chloride (0.034 g, 0.179 mmol) and stirring wascontinued at room temperature for 24 h during which time a quantitativeconsumption of 186 was noticed by TLC (CH₂Cl₂/MeOH 9:1, Rf=0.52). Thereaction was quenched with H₂O/THF 10:1 within 30 min and thenpartitioned between 10% NaHCO₃ (15 mL) and CH₂Cl₂ (20 mL). The twolayers were separated; the organic layer was washed with saturated brine(3×15 mL) and dried over Na₂SO₄. The solvent was evaporated, and thecrude was purified on a silica gel column eluting with 0–3% MeOH inCH₂Cl₂ to provide 202 (0.031 g, 80%).

Synthesis of Tetrazole 187

Compound 187 was made from des(N-methyl)-azithromycin 171 andtosyltetrazole 202 using method B as described for compound 149. Datafor 187: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.40 (dd, J=14, 3 Hz, 1H),6.98 (dd, J=9, 2 Hz, 1H), 6.84 (t, J=9 Hz, 1H), 5.05 (m, 1H), 4.62–4.65(m, 3H), 4.34 (d, J=7 Hz, 1H), 4.19 (bs, 1H), 3.80 (t, J=5 Hz, 4H), 2.98(t, J=5 Hz, 4H), 0.82 (t, J=7 Hz, 3H).

Example 14 Synthesis of Compounds 203 and 204

Scheme 40 below depicts the synthesis of compounds 203 and 204. Knownazide 253 (see: International Patent Application WO 03/035648) wascoupled to 4-hydroxymethylphenylboronic acid to yield biaryl azide 254.Cycloaddition of 254 to alkynes 173 and 197 delivers macrolide targets203 and 204 respectively.

Synthesis of Biaryl Azide 254

Azide 253 (0.300 g, 0.830 mmol), and 4-hydroxymethylphenylboronic acid(0.152 g, 1.00 mmol) were dissolved in toluene. Potassium carbonate(0.345 g, 2.50 mmol), tetrakis(triphenylphosphine)palladium (0.040 g,0.035 mmol), ethanol (3 mL) and water (3 mL) were added, and thereaction was degassed thrice before being heated to reflux for twohours. The reaction was allowed to cool to room temperature, and thenwas partitioned between ethyl acetate (10 mL) and water (10 mL). Thelayers were separated, and the aqueous phase extracted with ethylacetate (2×10 mL). The combined organic layers were washed with water(10 mL) and brine (10 mL). The organic layer was dried with MgSO₄, andevaporated. The crude was purified on silica gel column eluting with20–50% EtOAc in CH₂Cl₂ to provide 254 (0.163 g, 0.476 mmol; 57% yield).

Synthesis of Triazole 203

This compound was obtained from the reaction of alkyne 173 (0.075 g,0.095 mmol) with azide 254 (0.049 g, 0.143 mmol) in the presence of CuI(0.029 g, 0.143 mmol) in THF (3 mL) and i-Pr₂NEt (0.6 mL) at roomtemperature within 6 h. The crude reaction was concentrated and thenpurified on silica gel eluting with CH₂Cl₂/MeOH/NH₄OH 30:1:0.05 to25:1:0.05 to 20:1:0.05 to 18:1:0.05 to 15:1:0.05 to give 203 as a whitesolid. Data for 203: MS (ESI) m/z 1129.4 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃,partial): δ 7.65 (s, 1H), 7.53–7.33 (m, 6H), 7.19 (d, J=8 Hz, 1H), 5.03(m, 2H), 4.70–4.76 (m, 5H), 4.42 (d, J=7 Hz, 1H), 4.28 (d, J=3 Hz, 1H),4.06 (m, 3H), 3.67 (m, 2H), 3.43 (m, 1H), 0.82 (m, 7H).

Synthesis of Triazole 204

A solution of alkyne 197 (100 mg, 0.127 mmol) in tetrahydrofuran (3.0mL) was treated with azide 254 (50 mg, 0.15 mmol), i-Pr₂NEt (0.664 mL,3.81 mmol) and copper (I) iodide (48.4 mg, 0.254 mmol), and the mixturewas stirred under argon at room temperature for 15 h. The reactionmixture was diluted with methylene chloride (50 mL), washed withsaturated aqueous NH₄Cl (3×50 mL), and brine (2×50 mL). The organicphase was dried (Na₂SO₄), and evaporated. The residue waschromatographed on silica gel using a 4–10% gradient of methanol inchloroform as eluant to provide 69 mg of pure product 204 as a whitepowder. Data for 204: MS (ESI) m/z 1128.5 (M+H)⁺, 1150.4 (M+Na)⁺. ¹HNMR(300 MHz, CDCl₃, partial): δ 7.72 (s, 1H), 7.52–7.38 (m, 6H), 7.17 (dd,J=8, 2 Hz, 1H) 5.06–5.03 (m, 2H), 4.92 (d, J=4 Hz, 1H), 4.42 (d, J=7 Hz,1H), 4.18 (t, 1H), 0.82 (t, J=7 Hz, 3H).

Example 15 Synthesis of Compound 205

Scheme 41 depicts the synthesis of compound 205. Available amine 255 wasbis-silylated and the amine alkylated to afford diethyl amine derivative256. The nitro group of 256 was reduced and the resultant amineconverted to the benzyl carbamate 257. Conversion of 257 via standardmethods to the oxazolidinone 258 was followed by formation of the azides259 and 260. Azide 260 was treated with alkyne 173 to afford thetriazole cycloadduct which was subsequently desilylated to affordcompound 205.

Synthesis of Amine 256

To a suspension of amine 255 (2.00 g, 9.33 mmol) in a 1.0 M CH₂Cl₂solution of TBSCl (22.40 mL, 22.40 mmol) and anhydrous CH₃CN (10 mL) wasadded DBU (2.96 mL, 19.56 mmol) at 0° C. A clear homogenous solutionresulted within a few minutes of the DBU addition and the reaction wasstirred at room temperature for 24 h. The reaction was poured intoCH₂Cl₂ (60 mL) and extracted with saturated NaHCO₃ (3×30 mL), saturatedNH₄Cl (2×30 mL), saturated brine, and then the organic phase was driedover Na₂SO₄. The solvent was evaporated to give a light yellow oil whichwas used without further purification.

To a solution of the crude product obtained above (2.00 g, 4.54 mmol) inTHF (25 mL) and i-Pr₂NEt (10 mL) was added iodoethane (5.00 mL, 61.35mmol) and the mixture was heated between 70° C. to 75° C. for 48 h. Thereaction was worked-up as described in the first step above. The crudewas purified on silica gel eluting with hexanes/EtOAc 12:1 to 8:1 togive compound 256 as a light yellow oil (1.16 g, 51%). Data for 256:¹H-NMR, (300 MHz, CDCl₃): δ 8.08 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H),4.99 (d, J=3 Hz, 1H), 3.79 (m, 1H), 3.65 (m, 1H), 2.59 (m, 2H), 2.48 (m,1H), 2.37 (m, 2H), 0.86 (s, 9H), 0.84 (s, 9H), 0.63 (t, J=7 Hz, 6H),0.00 (bs, 9H), −0.29 (s, 3H).

Synthesis of Carbamate 257

Compound 256 (1.16 g, 2.34 mmol) was dissolved in absolute EtOH (30 mL)and THF (6 mL). To this solution was added Pd—C (10 wt %, Degussa, 0.11g) and the reaction was kept under a hydrogen environment using aballoon. TLC after stirring for 48 h revealed a complete consumption ofstarting material. The reaction was filtered and the filtrate evaporatedto give a yellow oil. The crude oil was dissolved in acetone (30 mL) andwater (10 mL). The resulting mixture was kept at 0° C. while NaHCO₃(0.46 g, 5.5 mmol) and CBZCl (0.42 mL, 2.81 mmol) were added. Thereaction was allowed to warm up to room temperature and stirred for 4 h.The reaction was poured into CH₂Cl₂ (60 mL) and extracted with saturatedNaHCO₃ (3×30 mL), saturated NH₄Cl (2×30 mL), and the organic phase wasdried over Na₂SO₄. The solvent was evaporated to give a yellow oil. Thecrude was purified on silica gel column, eluting with 1–4% MeOH inCH₂Cl₂ to give 257 as a yellow oil (1.02 g, 72%). Data for 257: ¹H-NMR(300 MHz, CDCl₃): δ 7.37–28 (m, 9H), 5.17 (s, 2H), 4.84 (d, J=4 Hz, 1H),3.77 (m, 1H), 3.60 (m, 1H), 2.69–2.43 (m, 5H), 0.88 (s, 9H), 0.85 (s,9H), 0.75 (t, J=7 Hz, 6H), 0.00 (bs, 9H), −0.29 (s, 3H).

Synthesis of Alcohol 258

Carbamate 257 (1.02 g, 1.69 mmol) was dissolved in anhydrous THF (10 mL)and the solution was cooled to −78° C. n-Butyllithium (2.5 M in Hexanes)(0.87 mL, 2.18 mmol) was added and the reaction was maintained at −78°C. for 1 h. (R)-Glycidyl butyrate (0.31 mL, 2.184 mmol) was added, thereaction was allowed to warm up to room temperature and stirred forabout 16 h. The reaction was partitioned between saturated NH₄Cl (30 mL)and CH₂Cl₂ (50 mL). The organic layer was washed with saturated NH₄Cl(2×30 mL), saturated brine (1×30 mL), and then dried over Na₂SO₄. Thesolvent was evaporated, and the residue was dissolved in MeOH (20 mL)containing a catalytic amount of sodium methoxide, and the solution wasstirred at room temperature for 45 min. The solvent was evaporated, thecrude was taken up into CH₂Cl₂ (50 mL) and extracted with saturatedNH₄Cl (2×30 mL). The organic phase was dried over Na₂SO₄ andconcentrated. The residue was purified on silica gel column, elutingwith 5–6% MeOH in CH₂Cl₂ to give 258 as a white foam (0.53 g, 56%). Datafor 258: ¹H-NMR (300 MHz, CDCl₃): δ 7.52 (d, J=9 Hz, 2H), 7.41 (d, J=9Hz, 2H), 4.87 (d, J=3 Hz, 1H), 4.70 (m, 1H), 4.02–3.92 (m, 3H), 3.76 (m,2H), 3.62 (m, 1H), 2.63–2.43 (m, 5H), 0.88 (s, 9H), 0.85 (s, 9H), 0.74(t, J=7 Hz, 6H), 0.00 (bs, 9H), −0.28 (s, 3H).

Synthesis of Azides 259 and 260

To a solution of oxazolidinone 258 (0.53 g, 0.935 mmol) in anhydrousCH₂Cl₂ (15 mL) and Et₃N (0.28 mL, 2.00 mmol) at 0° C. was added MsCl(0.14 mL, 1.8 mmol). The reaction was stirred at 0° C. for 2 h and thereaction was poured into saturated NaHCO₃ (30 mL) and CH₂Cl₂ (50 mL) andthe two layers were separated. The organic layer was extracted with H₂O(2×30 mL), saturated brine (1×30 mL), and dried over Na₂SO₄. The solventwas evaporated to give a yellow oil. The crude was taken up in DMF (10mL), NaN₃ (0.24 g, 3.74 mmol) was added, and the reaction was heated at75° C. for 24 h. Water (40 mL) was added and the reaction was extractedwith EtOAc (3×40 mL). The combined organic layer was extracted withsaturated brine (1×50 mL) and dried over Na₂SO₄. The solvent wasevaporated and the crude was purified on a silica gel column elutingwith 1–6% MeOH in CH₂Cl₂ to give azide 259 (0.378 g) and azide 260(0.027 g). Data for azide 259: ¹H-NMR (300 MHz, CDCl₃): δ 7.54 (d, J=9Hz, 2H), 7.41 (d, J=9 Hz, 2H), 4.87 (d, J=3 Hz, 1H), 4.70 (m, 1H),4.02–3.92 (m, 3H), 3.77–3.74 (m, 2H), 3.62 (m, 1H), 2.63–2.43 (m, 5H),0.88 (s, 9H), 0.85 (s, 9H), 0.71 (t, J=7 Hz, 6H), 0.00 (bs, 9H), −0.28(s, 3H). Data for azide 260: MS (ESI) m/z 478.1 (M+H)⁺; ¹H-NMR (300 MHz,CDCl₃): δ 7.59 (d, J=9 Hz, 2H), 7.49 (d, J=9 Hz, 2H), 4.86 (m, 1H), 4.46(d, J=10 Hz, 1H), 4.20 (t, J=9 Hz, 1H), 3.95 (m, 1H), 3.81–3.61 (m, 4H),2.98–2.94 (m, 2H), 2.79–2.71 (m, 3H), 1.22 (t, J=7 Hz, 6H), 0.93 (s,9H), 0.00 (s, 3H), 0.00 (s, 3H).

Synthesis of Compound 205

Alkyne 173 (0.038 g, 0.045 mmol) and azide 260 (0.027 g, 0.057 mmol)were subjected to the cycloaddition reaction in the presence of CuI(0.029 g, 0.143 mmol) in THF (3 mL) and i-Pr₂NEt (0.6 mL) at roomtemperature for 2h. The reaction was poured into a mixture containingsaturated NH₄Cl/NH₄OH (pH=9.5, 30 mL) and extracted with CH₂Cl₂ (3×30mL). The combined organic layer was dried over Na₂SO₄ and the solventevaporated. The crude was purified on silica gel eluting withCH₂Cl₂/MeOH/OH 15:1:0.05 to give a white solid (0.048 g).

The product obtained above (0.047 g) was dissolved in CH₂Cl₂ (2 mL) anda freshly prepared solution of 1.34 MN,N,N′N′-tetramethylethylenediamine hydrofluoride (TEMED.HF) inacetonitrile (0.5 mL, 0.67 mmol) was added. Stirring was continued for 3h and the reaction was concentrated. The crude was purified on a silicagel column, eluting with CHCl₃/MeOH/NH₄OH 15:1:0.05 to give a slightlyimpure white solid. This was re-purified on a second silica gel columneluting with CH₂Cl₂/MeOH/NH₄OH 18:1:0.04 to 16:1:0.04 to give 205 as awhite solid (0.018 g). Data for 205: MS (ESI) m/z 1172.5 (M+Na)⁺; ¹H-NMR(300 MHz, CDCl₃, partial): δ 7.61 (s, 1H), 7.25–7.17 (m, 4H), 4.89 (m,2H), 4.58 (m, 3H), 4.17 (d, J=9 Hz, 1H), 4.04 (m, 2H), 3.76 (m, 1H),3.46–3.31 (m, 4H), 2.85 (d, J=9 Hz, 1H), 0.75 (m, 7H).

Example 16 Synthesis of Compounds 206 and 207

Scheme 42 depicts the synthesis of targets 206 and 207. The aromaticsubstitution reaction of 3,4-difluoronitrobenzene and2-(methylamino)ethanol provided nitroaniline 261. The alcohol of 261 wasprotected and the nitro group was reduced to afford amine 262.Conversion of 262 to carbamate 263 was followed by synthesis of theoxazolidinone 264. Alcohol 264 was converted to azides 265 and 266, andthe latter was acylated to afford azide 267. The cycloaddition of 266and 267 with alkyne 173 afforded targets 206 and 207 respectively.

Synthesis of Amine 261

To a solution of 3,4-difluoronitrobenzene (2.4 mL, 29.72 mmol) in EtOAc(20 mL) and i-Pr₂NEt (5.1 mL, 29.30 mmol) was slowly added2-(methylamino)ethanol (3 mL, 27.10 mmol) at 0° C. The reaction wasallowed to warm up to room temperature and stirring was continuedovernight. The reaction was poured into EtOAc (30 mL) and extracted withH₂O (50 mL). The aqueous layer was basified with KOH pellets (pH 10.0)and extracted with CH₂Cl₂ (3×30 mL). The combined organic layer wasdried over Na₂SO₄ and the solvent evaporated to give a yellow solidresidue. The crude was dissolved in 6 N HCl (60 mL) at 0° C., extractedwith CH₂Cl₂ (3×30 mL), and the organic layer was back extracted with 0.6N HCl (25 mL). The combined acid layer was basified with KOH pellets at0° C. and extracted with CH₂Cl₂ (4×40 mL). The organic phase was driedover Na₂SO₄ and the solvent evaporated to give 261 as a yellow solid(R_(f)=0.56, CH₂Cl₂/MeOH, 4.59 g, 79%). Data for 261: MS (ESI) m/z 214.7(M+H)⁺.

Synthesis of Amine 262

Compound 261 (4.5 g, 21 mmol), imidazole (2.91 g, 42 mmol) and DMAP(0.26 g, 2.1 mmol) were dissolved in anhydrous CH₂Cl₂ (50 mL). To thissolution was added TBSCl (3.33 g, 22.10 mmol) and stirring was continuedfor 2 h. CH₂Cl₂ (30 mL) was added and the mixture was extracted withsaturated NaHCO₃ (2×50 mL) and saturated brine (1×50 mL). The organicphase was dried over Na₂SO₄ and evaporated to give a yellow oil. The oilwas dissolved in absolute EtOH (50 mL) and THF (10 mL). To this solutionwas added Pd—C (10 wt %, Degussa, 0.50 g) and the reaction was keptunder a hydrogen environment using a balloon. TLC after stirring for 24h revealed a complete consumption of starting material. The reaction wasfiltered and the filtrate evaporated to give 262 as a red oil which wasused in further reactions without further purification. Data for 262: MS(ESI) m/z 298.7 (M+H)⁺.

Synthesis Of Oxazolidinone 264

Crude oil 262 was dissolved in acetone (60 mL) and water (20 mL). Theresulting mixture was kept at 0° C., and NaHCO₃ (4.13 g, 49.40 mmol) andCBZCl (3.77 mL, 25.22 mmol) were added. The reaction was allowed to warmup to room temperature and stirring continued for 2 h. The reaction waspoured into CH₂Cl₂ (120 mL) and extracted with saturated NaHCO₃ (2×50mL) and saturated brine (1×50 mL). The organic phase was dried overNa₂SO₄ and evaporated to give carbamate 263 as a red oily residue.

The crude 263 above was dissolved in anhydrous THF (50 mL) and thesolution was cooled to −78° C. n-Butyllithium (2.5 M in Hexanes) (10.8mL, 27 mmol) was added and the reaction was maintained at −78° C. for 1h. (R)-Glycidyl butyrate (3.83 mL, 27 mmol) was added, the reaction wasallowed to warm up to room temperature, and stirring was continued forabout 16 h. The reaction was poured into EtOAc (100 mL), extracted withsaturated NaHCO₃ (2×60 mL) and saturated brine (1×60 mL). The organicphase was dried over Na₂SO₄ and evaporated. The residue was dissolved inMeOH (50 mL) containing sodium methoxide (25% wt/vol in MeOH, 0.3 mL)and the solution was stirred at room temperature for 30 min. The solventwas evaporated, and the crude was poured into EtOAc (100 mL), and washedwith saturated NaHCO₃ (1×60 mL) and saturated brine (1×60 mL). Theorganic phase was dried over Na₂SO₄ and evaporated to give a brown oilyresidue. The residue was purified on a silica gel column, eluting withCH₂Cl₂/MeOH 25:1 to 20:1 to give 264 as a brown solid (5.93 g, 71%).Data for 264: MS (ESI) m/z 399.0 (M+H)⁺.

Synthesis of Azides 265 and 266

To a solution of oxazolidinone 264 (3.00 g, 7.54 mmol) in anhydrousCH₂Cl₂ (40 mL) and Et₃N (2.16 mL, 15.45 mmol) at 0° C. was added MsCl(1.03 mL, 13.20 mmol). The reaction was stirred at 0° C. for 2 h andthen was poured into saturated NaHCO₃ (60 mL) and CH₂Cl₂ (100 mL) andthe two layers separated. The organic layer was extracted with H₂O (2×40mL), saturated brine (1×40 mL) and dried over Na₂SO₄. The solvent wasevaporated to give a brown oil. The crude was taken up in DMF (25 mL),then NaN₃ (2.00 g, 30.16 mmol) was added and the reaction was kept at70° C. for 18 h. Water (60 mL) and EtOAc (100 mL) were added and the twolayers separated. The aqueous layer was extracted with EtOAc (2×50 mL),and the combined organic layer was dried over Na₂SO₄ and evaporated. Thecrude was purified on a silica gel column, eluting with CH₂Cl₂/MeOH 30:1to 24:1 to 20:1 to give azide 265 (2.16 g, 68%, white solid) and azide266 (0.33 g, 14%, brown foam). Data for azide 265: MS (ESI) m/z 424.0(M+H)⁺; ¹H-NMR (300 MHz, CDCl₃): δ 7.35 (dd, J=15, 3 Hz, 1H), 7.06 (dd,J=9, 2 Hz, 1H), 6.88 (m, 1H), 4.75 (m, 1H), 4.02 (t, J=9 Hz, 1H),3.81–3.74 (m, 3H), 3.67 (dd, J=13, 5 Hz, 1H), 3.57 (dd, J=13, 4 Hz, 1H),3.28 (t, J=6 Hz, 2H), 2.90 (s, 3H), 0.85 (s, 9H), 0.01 (s, 6H). Data forazide 266: MS (ESI) m/z 309.8 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃): δ 7.37(dd, J=15, 3 Hz, 1H), 7.06 (dd, J=9, 3 Hz, 1H), 6.94 (t, J=6 Hz, 1H),4.77 (m, 1H), 4.03 (t, J=9 Hz, 1H), 3.80–3.56 (m, 5H), 3.20 (t, J=6 Hz,2H), 2.81 (s, 3H).

Synthesis of Azide 267

To a solution of azide 266 (0.16 g, 0.52 mmol) in THF (5 mL) and Et₃N(0.10 mL, 0.68 mmol) was added Ac₂O (0.065 mL, 0.68 mmol) and a fewgrains of DMAP at room temperature. Stirring was continued for 3 h, thenthe reaction was quenched with aqueous MeOH, poured into NaHCO₃ (30 mL),and extracted with CH₂Cl₂ (50 mL). The CH₂Cl₂ layer was extracted oncewith saturated brine (30 mL) and dried over Na₂SO₄. The solvent wasevaporated to give 267 as a brown oil (0.182 g, 99%). MS (ESI) m/z 351.9(M+H)⁺.

Synthesis of Triazole 206

This compound was obtained from the reaction of alkyne 173 (0.315 g,0.40 mmol) with azide 266 (0.16 g, 0.52 mmol) in the presence of CuI(0.057 g, 0.30 mmol) in THF (10 mL) and i-Pr₂NEt (0.1 mL) at roomtemperature within 30 min under argon. Saturated NH₄Cl (30 mL) wasadded, and stirring was continued for 5 min. The reaction was basifiedwith NH₄OH to pH 9.0. CH₂Cl₂ (40 mL) was added, the two layers wereseparated, and the aqueous layer was extracted with CH₂Cl₂ (2×25 mL).The combined organic layer was dried over Na₂SO₄ and the solventevaporated. The crude was purified on silica gel eluting withCH₂Cl₂/MeOH/NH₄OH 18:1:0.05 to 15:1:0.05 to 12:1:0.05 to give 206 as awhite solid (0.426 g, 97%). Data for 206: MS (EST) m/z 1096.4 (M+H)⁺;¹H-NMR (300 MHz, CDCl₃, partial): δ 7.61 (s, 1H), 7.24 (dd, J=15, 2 Hz,1H), 6.90 (m, 2H), 5.00 (m, 2H), 4.69 (m, 3H), 4.43 (d, J=7 Hz, 1H),4.24 (m, 2H), 3.88 (m, 1H), 3.74 (t, J=5 Hz, 2H), 0.88 (m, 7H).

Synthesis of Triazole 207

This compound was obtained from the reaction of alkyne 173 (0.315 g,0.40 mmol) with azide 267 (0.182 g, 0.52 mmol) as described for triazole206 above. The crude was purified on silica gel, first eluting withCH₂Cl₂/MeOH 18:1 to remove unreacted 267, then with CH₂Cl₂/MeOH 15:1 to12:1 to 10:1 containing a trace amount of NH₄OH to give 207 as a whitesolid (0.42 g, 92%). Data for 207: MS (ESI) m/z 1138.3 (M+H)⁺; ¹H-NMR(300 MHz, CDCl₃, partial): δ 7.62 (s, 1H), 7.29 (dd, J=15, 2 Hz, 1H),6.93 (m, 1H), 6.85 (t, J=9 Hz, 1H), 5.01 (m, 2H), 4.66 (m, 3H), 4.22 (t,J=6 Hz, 2H), 3.89 (m, 1H), 3.38 (t, J=6 Hz, 2H), 0.89 (m, 7H).

Example 17 Synthesis of Triazole 208

Scheme 43 depicts the synthesis of triazole 208. Azide 188 was convertedto benzylic alcohol 268, which was subsequently converted to triazole208 using the copper-catalyzed cycloaddition chemistry described above.

Synthesis of Azide 268

A solution of azide 188 (0.38 g, 1.43 mmol) in anhydrous THF (5 mL) wascooled to −78° C. To this solution was slowly added 1 M methylmagnesiumbromide (CH₃MgBr) in butyl ether (1.5 mL, 1.50 mmol) within 20min. The reaction was allowed to warm up to room temperature andstirring was continued for 3 h. The reaction was quenched with H₂O (20mL) and extracted with CH₂Cl₂ (40 mL). The organic layer was extractedwith saturated brine (25 mL), dried over Na₂SO₄ and the solventevaporated. The crude was purified on silica gel eluting withEtOAc/Hexanes 3:1 to 5:1 to give azide 268 as a white foam (0.178 g,45%). Data for 268: MS (ESI) m/z 276.8 (M+H)⁺.

Synthesis of Triazole 208

This compound was obtained from the reaction of alkyne 173 (0.20 g, 0.25mmol) with azide 268 (0.095 g, 0.34 mmol) as described for triazole 206above except that the reaction was first quenched with saturatedNH₄Cl/NH₄OH 5:1 (pH=9.5, 30 mL) before the usual CH₂Cl₂ extraction. Thecrude was purified on silica gel, first eluting with CH₂Cl₂/MeOH 12:1,then with CH₂Cl₂/MeOH/NH₄OH 15:1:0.05 to 12:1:0.05 to give 208 as awhite solid (0.056 g). Data for 208: MS (ESI) m/z 1063.4 (M+H)⁺; ¹H-NMR(300 MHz, CDCl₃, partial): δ 7.63 (s, 1H), 7.48 (d, J=9 Hz, 2H), 7.37(d, J=9 Hz, 2H), 5.03 (m, 2H), 4.72 (m, 3H), 4.44 (d, J=7 Hz, 1H), 4.30(d, J=5 Hz, 1H), 4.16 (t, J=9 Hz, 1H), 3.92 (m, 1H), 3.67 (m, 2H), 0.90(m, 7H).

Example 18 Synthesis of Triazole 209

Scheme 44 shows the synthesis of triazole 209. 3-Aminopyridine wasconverted to carbamate 269 which was subsequently transformed to azide271 using chemistry similar to that reported above. Cycloaddition of 271with alkyne 173 yielded triazole 209.

Synthesis of Alcohol 270

Oxazolidinone 270 was synthesized from 3-aminopyridine using thechemistry reported for the conversion of amine 262 to alcohol 264(Example 16). The crude was purified on silica gel column, eluting withCH₂Cl₂/MeOH 19:1 to give 270 as a white solid (46%). Data for 270: MS(ESI) m/z 194.7 (M+H)⁺.

Synthesis of Azide 271

Azide 271 was synthesized from alcohol 270 as described for thesynthesis of azides 259 and 260 (Example 15) except that the sodiumazide reaction with the intermediate mesylated derivative of 270 wascomplete within 2 h. The reaction was worked-up with saturated NaHCO₃(30 mL) and EtOAc (4×40 mL). The organic phase was dried over Na₂SO₄ andevaporated. The crude was purified on silica gel, eluting withCH₂Cl₂/MeOH 17:1 to give 271 as a colorless, thick oil (81%). Data for271: MS (ESI) m/z 220.0 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃): δ 8.60 (d, J=2Hz, 1H), 8.35 (dd, J=5, 1 Hz, 1H), 8.07 (m, 1H), 7.28 (dd, J=8, 5 Hz,1H), 4.83 (m, 1H), 4.11 (t, J=9 Hz, 1H), 3.87 (dd, J=9, 6 Hz, 1H), 3.72(dd, J=14, 4 Hz, 1H), 3.57 (dd, J=14, 5 Hz, 1H).

Synthesis of Triazole 209

This compound was obtained from the reaction of alkyne 173 (0.17 g, 0.22mmol) with azide 271 (0.080 g, 0.36 mmol) as described for triazole 206above (Example 16) except that the reaction was allowed to stir for 12h. The crude was purified on silica gel, first eluting with CH₂Cl₂/MeOH17:1, then with CH₂Cl₂/MeOH/NH₄OH 17:1:0.05 to 15:1:0.05 to 12:1:0.05 to10:1:0.05 to give 209 as a white solid (0.117 g, 54%). Data for 209: MS(ESI)m/z 1006.5 (M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 8.67 (d, J=3Hz, 1H), 8.36 (dd, J=5, 1 Hz, 1H), 7.84 (m, 1H), 7.62 (s, 1H), 7.28 (m,1H), 5.16–5.05 (m, 2H), 4.75 (d, J=4 Hz, 2H), 4.45 (d, J=7 Hz, 1H), 3.64(t, J=7 Hz, 1H), 0.88 (m, 7H).

Example 19 Synthesis of Triazole 210

Triazole 210 was synthesized by dealkylation of compound 149 (Scheme45).

Synthesis of Triazole 210

Compound 149 (0.20 g, 0.183 mmol) and NaOAc (0.15 g, 1.83 mmol) weredissolved in 80% aqueous MeOH (5 mL), and the mixture was heated undergentle reflux for 1 h. The reaction was allowed to cool to roomtemperature and H₂O/NH₄OH 8:1 (9 mL) was added. The mixture wasextracted with CH₂Cl₂ (3×20 mL), the combined organic layer wasextracted with H₂O/NH₄OH 5:1 (20 mL), dried over Na₂SO₄ and the solventevaporated. The crude was purified on silica gel eluting withCH₂Cl₂/MeOH/H₂O (containing a trace of NH₄OH) 20:1:0.05 to 18:1:0.05 to15:1:0.05 to 12:1:0.05 to give 210 as a white solid (0.049 g). Data for210: MS (ESI) m/z 1079.4 (M+Na)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ7.55 (s, 1H), 7.25 (dd, J=14, 2 Hz, 1H), 6.91 (dd, J=9, 2 Hz, 1H), 6.82(t, J=9 Hz, 1H), 4.96 (m, 2H), 4.81 (d, J=4 Hz, 1H), 4.64 (m, 2H), 4.31(d, J=7 Hz, 1H), 4.05 (t, J=9 Hz, 1H), 3.47 (d, J=7 Hz, 2H), 2.29–2.25(m, 2H), 0.78 (t, J=7 Hz, 3H).

Example 20 Synthesis of Triazole 211

A solution of alkyne 198 (136 mg, 0.216 mmol) in tetrahydrofuran (3.0mL) was treated with azide 158 (104 mg, 0.325 mmol), i-Pr₂NEt (1.1 mL,6.58 mmol) and copper (I) iodide (82 mg, 0.432 mmol), and the mixturewas stirred under argon at room temperature for 15 h. The reactionmixture was diluted with methylene chloride (50 mL), washed withsaturated aqueous NH₄Cl (3×50 mL), and brine (2×50 mL). The organicphase was dried (Na₂SO₄), and evaporated. The residue waschromatographed on silica gel using a 4–10% gradient of methanol inmethylene chloride as eluant to provide 211 as a white solid (0.112 g,0.118 mmol, 56%). Data for 211: MS (ESI) m/z 949.3 (M+H)⁺; ¹HNMR (300MHz, CDCl₃, partial): δ 7.68 (s, 1H), 7.33 (dd, J=2, 14 Hz, 1H), 6.97(dd, J=2, 9 Hz, 1H), 6.89 (t, J=9 Hz, 1H), 5.16 (dd, J=3, 11 Hz, 1H),5.09–4.99 (m, 1H), 4.72 (ddd, J=4, 15, 18 Hz, 2H), 4.36 (d, J=7 Hz, 1H),4.13 (t, J=9 Hz, 2H), 0.83 (t, J=7 Hz, 3H).

Example 21 Synthesis of Triazole 212

To a mixture of alkyne 201 (48 mg, 0.076 mmol), azide 189 (19.9 mg,0.084 mmol) and copper (I) iodide (8 mg, 0.038 mmol) was added THF (3mL) and the mixture was repeatedly degassed and flushed with argon. Theni-Pr₂NEt (0.1 mL) was introduced and the mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into NH₄Cl (30 mL)and stirred for few minutes. Then NH₄OH (3 mL) was added and the mixturewas extracted with methylene chloride (3×40 ml). The combined organiclayers were dried (Na₂SO₄), concentrated and flash chromatographed oversilica gel (methylene chloride: MeOH:NH₄OH=48:2:0.05) to provide 212 (55mg, 0.06 mmol, 79%). Data for 212: MS (ESI) m/z 862.3 (M+H)⁺; ¹HNMR (300MHz, CDCl₃, partial): δ 7.60 (s, 1H), 7.32 (m, 1H), 7.09 (dd, J=3, 9 Hz,1H), 6.85 (brt, 1H), 0.86 (t, J=7 Hz, 3H).

Example 22 Synthesis of Triazole 213

Scheme 46 illustrates the synthesis of triazole 213.3,4-Difluoronitrobenzene is converted to nitroaniline 272 via anaromatic substitution reaction. The nitro group of 272 is reduced toafford aniline 273 which is transformed to carbamate 274. Oxazolidinoneformation to provide 275 is followed by conversion to the azide to yield277. Cycloaddition of azide 277 with alkyne 173 afforded triazole 213.

Synthesis of Nitroaniline 272

3,4-Difluoronitrobenzene (3 mL, 27.1 mmol) was added to a solution ofdimethyl amine (15 mL, 29.8 mmol) and i-Pr₂NEt (5.2 ml, 29.8 mmol) inethyl acetate (20 mL) at 0° C. and the mixture was stirred at roomtemperature overnight. The yellow solution was concentrated andredissolved in methylene chloride (100 mL) and then washed with water(50 mL). The aqueous layer was basified with KOH pellets and backextracted with methylene chloride (2×50 mL). The combined organic layerafter evaporation afforded a yellow solid which was dissolved in 6N HCl(60 mL) at 0° C. and washed with methylene chloride (3×60 mL). Thesolution was basified with KOH pellets (pH 10) and extracted withmethylene chloride (3×100 mL). The combined organic phase was dried(Na₂SO₄) and concentrated to provide 272 (1.8 g). Data for 272: ¹HNMR(300 MHz, CDCl₃): δ 7.95 (dd, J=2, 8 Hz, 1H), 7.88 (dd, J=3, 14 Hz, 1H),6.72 (t,J=9 Hz, 1H), 3.10 (s, 6H).

Synthesis of Aniline 273

To a solution of nitroaniline 272 (1.7 g, 9.2 mmol) in EtOH and THF(2:1, 30 mL) was added 10% Pd—C (0.2 g) and the mixture was stirredovernight at room temperature under hydrogen atmosphere. It was filteredthrough a Whatman filter paper and the residue was washed with methylenechloride (4×25 mL). The combined organic layer was evaporated to provide273 (1.3 g). Data for 273: ¹HNMR (300 MHz, CDCl₃): δ 6.81 (t, J=11 Hz,1H), 6.46–6.37 (m, 2H), 2.73 (s, 6H).

Synthesis of Carbamate 274

To a solution of aniline 273 (1.3 g, 8.4 mmol) in a mixture of acetone(20 mL) and water (5 mL) was added NaHCO₃ (1.76 g, 21 mmol) at 0° C. andthe mixture was stirred for few minutes. Then benzyl chloroformate (1.5mL, 10.1 mmol) was added dropwise and the mixture was stirred at 0° C.for 1 h. The reaction mixture was concentrated and dissolved inmethylene chloride (50 mL). The organic layer was washed with brine(3×50 mL), dried (Na₂SO₄) and concentrated to provide 274 (2.4 g) ofsuitable purity for use in subsequent reactions. Data for 274: ¹HNMR(300 MHz, CDCl₃): δ 7.38–7.12 (m, 6H), 6.95 (brd, J=8 Hz, 1H), 6.84 (t,J=9 Hz, 1H), 6.57 (brs, 1H), 5.18 (s, 2H), 2.78 (s, 6H).

Synthesis of Oxazolidinone 275

To a solution of carbamate 274 (2.4 g, 8.3 mmol) in THF (80 mL) wasadded n-BuLi (4.32 mL, 2.5 M in hexane, 10.79 mmol) at −78° C. and themixture was stirred for 1 h. (R)-Glycidyl butyrate (1.5 mL, 10.87 mmol)was added and the reaction warmed to room temperature and allowed tostir overnight. The reaction was carefully poured into saturated NH₄Cl(70 mL) and extracted with EtOAc (3×100 mL). The combined organic layerswere washed with brine (1×200 mL), dried (Na₂SO₄) and concentrated.Flash chromatography over silica gel (60%–100% EtOAc in hexanes)provided 275 (2 g) 275 as a white solid. Data for 275: ¹HNMR (300 MHz,CDCl₃): δ 7.38 (dd, J=3, 15 Hz, 1H), 7.10 (dd, J=3, 9 Hz 1H), 6.88 (t,J=12 Hz, 1H), 4.75–4.71 (m, 1H), 4.02–3.93 (m, 3H), 3.79–3.75 (m, 1H),2.81 (s, 6H).

Synthesis of Azide 277

To alcohol 275 (900 mg, 3.54 mmol) in methylene chloride (35 mL) at 0°C. was added triethylamine (0.5 mL, 3.58 mmol) and methanesulfonylchloride (0.41 mL, 5.31 mmol). After stirring for 1 h at 0° C., thereaction was poured into water (100 mL) and extracted with methylenechloride (3×100 mL). The combined organic layers were washed with water(2×100 mL), dried (Na₂SO₄) and concentrated to yield 1.1 g of pureproduct 276. To a solution of mesylate 276 (1.1 g, 3.3 mmol) in DMF (15mL) was added sodium azide (646 mg, 9.9 mmol) and the reaction washeated at 75° C. overnight. The reaction was poured into water (100 mL)and extracted with EtOAc (3×100 mL). The combined organic layers werewashed with water (3×100 mL), dried (Na₂SO₄) and concentrated to providea solid. The material was further purified by flash chromatography oversilica gel (50% EtOAc in hexanes) to yield 858 mg of pure azide 277.Data for 277: ¹HNMR (300 MHz, CDCl₃): δ 7.38 (dd, J=3, 15 Hz, 1H), 7.10(dd, J=3, 9 Hz 1H), 6.89 (t, J=9 Hz, 1H), 4.78–4.75 (m, 1H), 4.01 (t,J=9 Hz, 1H), 3.81 (dd, J=6, 9 Hz, 1H), 3.69 (dd, J=5, 13 Hz, 1H), 3.58(dd, J=5, 13 Hz, 1H), 2.82 (s, 3H).

Synthesis of Triazole 213

To a mixture of alkyne 173 (200 mg, 0.254 mmol), azide 277 (85 mg, 0.305mmol) and copper (I) iodide (24 mg, 0.127 mmol) was added THF (10 mL)and the mixture was repeatedly degassed and flushed with argon. Theni-Pr₂NEt (0.1 mL) was introduced and the mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into NH₄Cl (30 mL)and stirred for few minutes. Then NH₄OH (3 mL) was added and the mixtureextracted with methylene chloride (3×40 ml). The combined organic layerswere dried (Na₂SO₄), concentrated and flash chromatographed over silicagel (methylene chloride: MeOH:NH₄OH=12:1;0.05) to provide 223 mg oftriazole 213. Data for 213: MS (ESI) m/z 1066.5 (M+H)⁺; ¹HNMR (300 MHz,CDCl₃, partial): δ 7.63 (s, 1H), 7.27 (dd, J=2, 8 Hz, 1H), 6.94 (dd,J=2, 9 Hz, 1H), 6.84 (t, J=9 Hz, 1H), 5.30–5.04 (m, 2H), 0.89 (t, J=7Hz, 3H).

Example 23 Synthesis of Isoxazole 214

Scheme 47 exemplifies the synthesis of isoxazole 214. Known alkyne 278(Zacharie, B. et al. J. Med. Chem. 1997, 40, 2883) was converted byhydroxylamine to hydroxyisoxazole 279. The Mitsunobu reaction of 279with alcohol 280 (synthesized from 3-fluoroaniline using the chemistryreported in the literature (Brickner, S. J. et al. J. Med. Chem. 1996,39, 673)) afforded isoxazole 281. Desilylation of 281 afforded alcohol282 which was subsequently converted to tosylate 283. Alkylation ofamine 171 with tosylate 283 yielded isoxazole 214.

Synthesis of Hydroxyisoxazole 279

To a solution of hydroxylamine hydrochloride (208 mg, 3.0 mmol) in MeOH(5 mL) was added 10% NaOH (3.14 mL, 7.85 mmol) solution followed by asolution of alkyne 278 (900 mg, 2.5 mmol) in MeOH (1.5 mL). The mixturewas stirred overnight at room temperature and was then acidified with 6NHCl (pH 2), saturated with sodium sulphate. The mixture was extractedwith diethyl ether (3×50 mL). The combined organic layers were washedwith water (3×100 mL), dried (Na₂SO₄), concentrated and chromatographedover silica gel (20% EtOAc in hexanes) to provide 280 mg pure isoxazole279 as a white solid. Data for 279: MS (ESI) nm/z 408.9 (M+CH₃CN)⁺;¹HNMR (300 MHz, CDCl₃): δ 7.62 (brd, 4H), 7.46–7.35 (m, 6H), 5.76 (s,1H), 3.91 (t, J=6 Hz, 2H), 2.86 (t, J=7 Hz, 2H), 1.03 (s, 9H).

Synthesis of Isoxazole 281

To a solution of isoxazole 279 (100 mg, 0.272 mmol), alcohol 280 (86 mg,0.408 mmol) and triphenyl phosphine (114 mg, 0.435 mmol) in THF (8 mL)was added diisopropyl azodicarboxylate (0.08 mL, 0.408 mmol) at −20° C.The solution was warmed to room temperature and stirred for 3 h. Themixture was concentrated and chromatographed over silica gel (25–30%EtOAc in hexanes) to provide 140 mg of 281. Data for 281: MS (ESI) m/z583.0 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.61 (dd, J=3, 9 Hz, 4H),7.48–7.32 (m, 9H), 6.85 (brt, 1H), 5.72 (s, 1H), 5.02–4.94 (m, 1H), 4.53(dd, J=4, 12 Hz, 1H), 4.46 (dd, J=5, 12 Hz, 1H), 4.16–4.09 (m, 2H), 3.93(t, J=6 Hz, 2H), 2.87 (t, J=6 Hz, 2H), 1.03 (s, 9H).

Synthesis of Isoxazole 282

To a solution of silyl ether 281 (140 mg, 0.25 mmol) in THF (5 mL) wasadded tetrabutylammonium fluoride (0.5 mL, 1M in THF) at 0° C. and themixture was stirred overnight at room temperature. The reaction mixturewas concentrated and dissolved in EtOAc (50 mL). The organic layer waswashed with brine (2×50 mL), dried (Na₂SO₄), concentrated andchromatographed over silica gel (70% EtOAc in hexanes) to provide 70 mgof 282. Data for 282: MS (ESI) m/z 322.8 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃):δ 7.45 (ddd, J=2, 5, 11 Hz, 1H), 7.30–7.21 (m, 2H), 6.88–6.82 (m, 1H),5.78 (s, 1H), 5.04–4.96 (m, 1H), 4.52 (dd, J=4, 12 Hz, 1H), 4.43 (dd,J=5, 11 Hz, 1H), 4.15 (t, J=9 Hz, 1H), 3.96 (dd, J=6, 9 Hz, 1H), 3.91(t, J=6 Hz, 2H), 2.91 (t, J=6 Hz).

Synthesis of Tosylate 283

p-Toluenesulfonyl chloride (71.5 mg, 0.375 mmol) was added to a solutionof isoxazole 282 (60 mg, 0.187 mmol), triethylamine (0.065 mL, 0.468mmol) and DMAP (cat.) in methylene chloride (5 mL) at 0° C. The mixturewas then allowed to stir at room temperature for 4 h. The reactionmixture was diluted with EtOAc (30 mL) and washed with brine (3×30 mL),dried (Na₂SO₄), concentrated and chromatographed over silica gel (50%EtOAc in hexanes) to yield 77.6 mg of pure tosylate 283. Data for 283:MS (ESI) m/z 476.9 (M+H)⁺, 498.9 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.76(d, J=9 Hz, 2H), 7.46 (ddd, J=2, 5, 11 Hz, 1H), 7.38–7.23 (m, 4H),6.89–6.83 (m, 1H), 5.73 (s, 1H), 5.04–4.96 (m, 1H), 4.52 (dd, J=4, 12Hz, 1H), 4.44 (dd, J=5, 11 Hz, 1H), 4.26 (t, J=6 Hz, 2H), 4.16 (t, J=9Hz, 1H), 3.96 (dd, J=6, 9 Hz, 1H), 3.02 (t, J=6 Hz, 2H), 2.45 (s, 3H).

Synthesis of Isoxazole 214

A suspension of N-desmethylazithromycin 171 (100 mg, 0.136 mmol),tosylate 283 (52 mg, 0.109 mmol), i-Pr₂NEt (3 mL) and NaI (cat.) in THF(4 mL) was heated to reflux for 72h. The reaction mixture wasconcentrated and chromatographed over silica gel (methylenechloride:MeOH:NH₄OH=12:1:0.01) to yield 7 mg of 214. Data for 214: MS(ESI) m/z 1039.1 (M+H)⁺, 1061.5 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃,partial): δ 7.46 (ddd, J=2, 5, 11 Hz, 1H), 7.38–7.23 (m, 2H), 6.86 (brt,1H), 5.72 (s, 1H), 5.08 (d, J=5 Hz, 1H), 5.02–4.96 (m, 1H), 4.68 (d, J=8Hz, 1H), 4.53 (dd, J=4, 11 Hz, 1H), 4.46 (dd, J=5, 9 Hz, 1H), 0.90 (t,J=6 Hz, 3H).

Example 24 Synthesis of Triazole 215

Scheme 48 exemplifies the synthesis of triazole 215. The cycloadditionof known azide 284 (see U.S. Pat. No. 6,124,334) and alkyne 173 affordedtriazole 215.

Synthesis of Triazole 215

A solution of alkyne 173 (0.100 g, 0.13 mmol) and azide 284 (0.046 g,0.19 mmol) in tetrahydrofuran (1.3 mL) was treated withN,N-diisopropylethylamine (0.670 mL, 3.8 mmol) and copper (I) iodide (36mg, 0.19 mmol) and the mixture was stirred under argon at 23° C. for 2.5h. The reaction mixture was diluted with saturated aqueous ammoniumhydroxide (10 mL) and extracted with dichloromethane (4×30 mL). Thecombined organic fractions were dried (Na₂SO₄), evaporated, and theresidue purified by flash chromatography (SiO₂, ammoniumhydroxide/methanol/dichloromethane 0.05:1:9) to provide 215 (53 mg,0.048 mmol, 38%) as a white powder. Data for 215: MS (ESI) m/z 545.0(M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.81 (s, 1H), 7.61–7.54 (m,1H), 7.39–7.33 (m, 1H), 7.21–7.15 (m, 1H), 6.99 (d, J=2 Hz, 2H), 6.34(d, J=1 Hz, 2H), 3.29 (s, 3H), 3.26 (s, 3H), 0.89–0.78 (m, 6H).

Example 25 Synthesis of Triazole 216

Scheme 49 depicts the synthesis of triazole 216. The known alcohol 285(see International Patent Application WO0306440) is converted bystandard chemistry to azide 287. This azide is coupled to4-cyanophenylboronic acid using the Suzuki reaction to afford biarylazide 288. Cycloaddition of 288 with alkyne 173 afforded triazole 216.

Synthesis of Mesylate 286

A solution of alcohol 285 (2.5 g, 7.4 mmol) in methylene chloride (40mL) was cooled to 0° C. under argon and treated with Et₃N (1.80 mL, 13.2mmol) and methanesulfonyl chloride (0.57 mL, 7.4 mmol). The reactionmixture was warmed to 23° C. for 0.5 h then washed with 1 M hydrochloricacid (50 mL), saturated aqueous sodium bicarbonate (50 mL) and saturatedaqueous sodium chloride (50 mL). Drying (Na₂SO₄) and evaporationprovided mesylate 286 (2.8 g, 6.7 mmol, 91%) as a white powder Data for286: ¹HNMR (300 MHz, DMSO-d₆): δ 7.85 (dd, J=9, 8 Hz, 1H), 7.57 (dd,J=11, 2 Hz, 1H), 7.22 (dd, J=9, 2 Hz, 1H), 5.07–5.00 (m, 1H), 4.53–4.48(m, 2H), 4.22–4.19 (m, 1H), 3.83 (dd, J=9, 6 Hz, 1H), 3.26 (s, 3H).

Synthesis of Azide 287

A solution of mesylate 286 (7.00 g, 16.8 mmol) in dimethylformamide (50mL) was treated with sodium azide (1.5 g, 23 mmol) and stirred at 50° C.under argon for 18 h. The reaction mixture was cooled to 20° C., pouredinto H₂O (400 mL) and stirred at 0° C. The resulting precipitate wasfiltered, washed with H₂O and dried under reduced pressure to provideazide 287 as a white powder (4.0 g, 11 mmol, 66%). Data for 287: ¹HNMR(300 MHz, CDCl₃): δ 7.71 (dd, J=9, 7 Hz, 1H), 7.48 (dd, J=10, 2 Hz, 1H),7.06 (dd, J=9, 2 Hz, 1H), 4.89–4.77 (m, 1H), 4.09–4.04 (m, 1H), 3.84(dd, J=9, 6 Hz, 1H), 3.73 (dd, J=13, 5 Hz, 1H), 3.61 (dd, J=13, 5 Hz,1H).

Synthesis of Azide 288

A solution of azide 287 (0.36 g, 1.0 mmol) in toluene/ethanol/H₂O(3:1:1, 10 mL) was treated with potassium carbonate (0.41 g, 3.0 mmol),4-cyanophenylboronic acid (0.18 g, 1.2 mmol) andtetrakis(triphenylphosphine)palladium (0.005 g, 0.05 mmol), and themixture was stirred under argon at 80° C. for 0.5 h. The reactionmixture was cooled to room temperature, diluted with ethyl acetate (50mL), washed with H₂O (3×50 mL), dried (Na₂SO₄), and evaporated. Flashchromatography (SiO₂, hexanes/ethyl acetate 1:1) provided azide 288(0.23 g, 0.67 mmol, 67%) as a white powder. Data for 288: ¹HNMR (300MHz, CDCl₃): δ 7.72–7.69 (m, 2H), 7.64–7.60 (m, 2H), 7.55 (dd, J=13, 2Hz), 7.46–7.41 (m, 1H), 7.35 (dd, J=9, 2 Hz), 4.87–4.78 (m, 1H),4.14–4.08 (m, 1H), 3.89 (dd, J=9, 6 Hz, 1H), 3.73 (dd, J=13, 5 Hz, 1H)3.61 (dd, J=13, 5 Hz, 1H).

Synthesis of Triazole 216

A solution of alkyne 173 (0.19 g, 0.24 mmol) and azide 288 (0.10 g, 0.30mmol) in tetrahydrofuran (5.0 mL) was treated withN,N-diisopropylethylamine (0.042 mL, 0.24 mmol) and copper (I) iodide(19 mg, 0.10 mmol) and the mixture was stirred under argon at 23° C. for0.5 h. The reaction mixture was diluted with saturated aqueous ammoniumhydroxide (10 mL) and extracted with dichloromethane (3×30 mL). Thecombined organic fractions were dried (Na₂SO₄) and evaporated, and theresidue purified by flash chromatography (SiO₂, ammoniumhydroxide/methanol/dichloromethane (0.05:1:9) to provide 216 (110 mg,0.098 mmol, 41%) as a white powder. Data for 216: MS (ESI) m/z 1125(M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.72–7.69 (m, 2H), 7.62 (s,1H), 7.60 (m, 2H), 7.49–7.44 (m, 1H), 7.42–7.37 (m, 1H), 7.22–7.19 (m,1H), 3.31 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 0.88–0.86 (m, 6H).

Example 26 Synthesis of Triazoles 217 and 218

Scheme 50 details the synthesis of triazoles 217 and 218. The knowncarbamate 289 (see J. Med. Chem. 2000, 43, 953) was deprotected toafford aniline 290. Diazotization of 290 afforded azide 291, which wassubsequently converted by cycloaddition chemistry with available alkynesto triazoles 292 and 295. Manipulation of these intermediates to azides294 and 297 was followed by cycloaddition with alkyne 173 to affordtriazoles 217 and 218 respectively.

Synthesis of Aniline 290

A solution of carbamate 289 (3.6 g, 7.9 mmol) in methanol (120 mL) wastreated with acetic acid (30 mL) and 10% Pd—C (1.0 g) and the mixturewas stirred under a balloon of hydrogen for 12 h at 23° C. The reactionmixture was filtered through a plug of SiO₂ and evaporated under reducedpressure, providing 290 (1.5 g, 6.6 mmol, 84%) as a pink-white solid.Data for 290: ¹HNMR (300 MHz, DMSO-d₆): δ 7.32 (dd, J=14, 3, Hz, 1H),6.99–6.95 (m, 1H), 6.75 (dd, J=10, 9 Hz, 1H), 4.99 (s, 2H), 4.66–4.58(m, 1H), 4.01–3.94 (m, 1H), 3.72 (dd, J=9, 6 Hz, 1H), 3.63 (dd, J=12, 4Hz, 1H), 3.50 (dd, J=12, 4 Hz, 1H).

Synthesis of Azide 291

A suspension of aniline 290 (0.56 g, 2.5 mmol) in H₂O (10 mL) was cooledto 0° C. and treated with concentrated hydrochloric acid (1.0 mL, 12.4mmol) and sodium nitrite (0.19 g, 2.8 mmol). A solution of sodium azide(0.24 g, 3.8 mmol) in H₂O (1.0 mL) was added after 1 h, and stirring at0° C. was continued for an additional 1 h. The reaction mixture wasdiluted with saturated aqueous sodium bicarbonate (20 mL) and extractedwith ethyl acetate (100 mL). The organic fraction was washed with H₂O(100 mL) dried (Na₂SO₄) and evaporated to an orange film. Data for 291:¹HNMR (300 MHz, CD₃OD): δ 7.51 (dd, J=14, 3 Hz, 1H), 7.19 (m, 1H), 7.03(m, 1H), 4.70–4.61 (m, 1H), 4.02–3.96 (m, 1H), 3.79 (m, 1H), 3.74 (m,1H).

Synthesis of Triazole 292

A solution of azide 291 (0.14 g, 0.56 mmol) and trimethylsilylacetylene(0.47 mL, 3.3 mmol) in dimethylformamide (4 mL) was stirred at 60° C.for 16 h. The reaction mixture was cooled to 23° C., concentrated underreduced pressure to a volume of 2.0 mL, and treated withtetrabutylamonium fluoride (1.5 mL of a 1.0 M solution intetrahydrofuran) and acetic acid (0.1 mL) and the mixture was stirredfor 12 h. Ethyl acetate (100 mL) was added and the solution was washedwith H₂O (3×75 mL), dried (Na₂SO₄) and evaporated to provide 292 (87 mg,0.31 mmol, 56%) as a brown foam that was used directly in the next step.

Synthesis of Azide 294

A solution of alcohol 292 (94 mg, 0.34 mmol) in dichloromethane (3.5 mL)was cooled to 0° C. and treated with triethylamine (0.095 mL, 0.68 mmol)and methanesulfonyl chloride (0.029 mL, 0.37 mmol). The reaction mixturewas stirred at 23° C. for 1 h, then diluted with ethyl acetate (150 mL)and washed with 1 M hydrochloric acid (2×75 mL), 10% aqueous sodiumcarbonate (75 mL), dried (Na₂SO₄), and evaporated. Flash chromatography(SiO₂, 50–100% ethyl acetate/hexanes) provided mesylate 293 (50 mg, 0.14mmol, 41%) as a yellow film. Data for 293: MS (ESI) m/z 357 (M+H)⁺;¹HNMR (300 MHz, CDCl₃): δ 8.11–8.09 (m, 1H), 8.04–7.98 (m, 1H), 7.88 (m,1H), 7.85 (dd, J=13, 2 Hz, 1H), 7.32–7.27 (m, 1H), 5.04–4.96 (m, 1H),4.54 (dd, J=12, 4 Hz, 1H), 4.47 (dd, J=12, 4 Hz, 1H), 4.26–4.20 (m, 1H),4.03 (dd, J=9, 6 Hz, 1H), 3.12 (s, 3H), 2.36 (s, 6H).

A solution of mesylate 293 (0.050 g, 0.15 mmol) in dimethylformamide(1.5 mL) was treated with sodium azide (0.018 g, 0.28 mmol) and stirredat 60° C. under argon for 12 h. The reaction mixture was cooled to 20°C., diluted with ethyl acetate (75 mL), washed with H₂O (3×50 mL), dried(Na₂SO₄), and evaporated under reduced pressure providing azide 294 as ayellow film (41 mg).

Synthesis of Triazole 217

A solution of crude azide 294 obtained above (0.038 g, 0.13 mmol) andalkyne 173 (0.079 g, 0.10 mmol) in tetrahydrofuran (5.0 mL) was treatedwith diisopropylethylamine (0.050 mL, 0.29 mmol) and copper (I) iodide(18 mg, 0.094 mmol) and stirred under argon at 23° C. for 1 h. Thereaction mixture was diluted with saturated aqueous ammonium hydroxide(10 mL) and extracted with dichloromethane (3×30 mL). The combinedorganic fractions were dried (Na₂SO₄); evaporated; an (the residuepurified by flash chromatography (SiO₂, ammoniumhydroxide/methanol/dichloromethane (0.05:1:9) to provide triazole 217(32 mg, 0.029 mmol, 29%) as a yellow foam. Data for 217: MS (ESI) m/z546 (M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.01 (d, J=1 Hz, 1H),7.88–7.83 (m, 1H), 7.79 (d, J=1 Hz, 1H), 7.68 (s, 1H), 7.60 (m, 1H),7.20 (m, 1H), 3.26 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 0.88–0.84 (m,6H).

Synthesis of Triazole 295

A solution of azide 291 (0.14 g, 0.56 mmol) andN,N-dimethylpropargylamine (0.30 mL, 2.6 mmol) in dimethylformamide (4mL) was treated with copper (I) iodide (0.030 g, 0.16 mmol) and stirredat 20° C. for 1 h. The reaction mixture was diluted with ethyl acetate(100 mL) and washed with 10% ammonium hydroxide (2×100 mL) and saturatedaqueous sodium chloride (100 mL), dried (Na₂SO₄) and evaporated. Flashchromatography of the crude material (SiO₂, ammoniumhydroxide/methanol/dichloromethane (0.05:1:9) provided triazole 295 (18mg, 0.054 mmol, 9.6%) as a yellow film. Data for 295: ¹HNMR (300 MHz,CDCl₃): δ 8.02–8.01 (m, 1H), 7.86–7.81 (m, 1H), 7.71 (dd, J=14, 2 Hz,1H), 7.33–7.27 (m, 1H), 4.83–4.76 (m, 1H), 4.15–4.04 (m, 2H), 4.02 (dd,J=9, 4 Hz, 1H), 3.78 (dd, J=13, 3 Hz, 1H), 3.73–3.71 (m, 2H), 2.36 (s,6H).

Synthesis of Azide 297

A solution of alcohol 295 (17 mg, 0.050 mmol) in dichloromethane (0.5mL) was cooled to 0° C. and treated with triethylamine (0.014 mL, 0.10mmol) and methanesulfonyl chloride (0.0043 mL, 0.056 mmol). The reactionmixture was stirred at 23° C. for 1 h, then diluted with ethyl acetate(100 mL) and washed with 10% aqueous sodium carbonate (2×100 mL), dried(Na₂SO₄) and evaporated. Flash chromatography (SiO₂, ammoniumhydroxide/methanol/dichlromethane (0.05:1:9) provided mesylate 296 (17mg, 0.041 mmol, 82%) as a yellow film. Data for 296: MS (ESI) m/z 414(M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 8.02–8.01 (m, 1H), 8.05–7.95 (m, 1H),7.83 (dd, J=13, 2 Hz, 1H), 7.31–7.27 (m, 1H), 5.04–4.97 (m, 1H), 4.54(dd, J=12, 4 Hz, 1H), 4.47 (dd, J=12, 4 Hz, 1H), 4.03 (dd, J=9, 6 Hz,1H), 3.70 (s, 2H), 3.12 (s, 3H), 2.36 (s, 6H).

A solution of the above mesylate 296 (0.017 g, 0.042 mmol) indimethylformamide (0.40 mL) was treated with sodium azide (0.006 g,0.848 mmol) and stirred at 60° C. under argon for 12 h. The reactionmixture was cooled to 20° C., diluted with ethyl acetate (75 mL), washedwith H₂O (3×50 mL), dried (Na₂SO₄), and evaporated under reducedpressure providing azide 297 as a white foam (15 mg).

Synthesis of Triazole 218

A solution of crude azide 297 (0.012 g, 0.033 mmol) and alkyne 173(0.021 g, 0.027 mmol) in tetrahydrofuran (1.4 mL) was treated withdiisopropylethylamine (0.014 mL, 0.13 mmol) and copper (I) iodide (4.7mg, 0.025 mmol) and stirred under argon at 23° C. for 1 h. The reactionmixture was diluted with saturated aqueous ammonium hydroxide (10 mL)and extracted with dichloromethane (3×30 mL). The combined organicfractions were dried (Na₂SO₄), evaporated, and the residue purified byflash chromatography (SiO₂, ammonium hydroxide/methanol/dichloromethane(0.05:1:9) to provide triazole 218 (12 mg, 0.010 mmol, 39%) as a yellowfoam. Data for 218: MS (ESI) m/z 574 (M+2H)₂+; ¹HNMR (300 MHz, CDCl₃,partial): δ 8.11 (m, 1H), 7.89–7.84 (m, 1H), 7.67 (s, 1H), 7.58 (m, 1H),7.20 (m, 1H), 3.22 (s, 3H), 2.38 (s, 6H), 2.31 (s, 3H), 2.23 (s, 3H),0.88–0.84 (m, 6H).

Example 27 Synthesis of Triazoles 219 and 220

Scheme 51 details the synthesis of triazoles 219 and 220. Iodoarylalcohol 285 is converted to nitrile 298 which is then transformed toazide 300 via mesylate 299. Cycloaddition of azide 300 and alkyne 173yielded triazole 219. Nitrile 298 was manipulated to oxadiazole 301,which served as the precursor to azide 302. Cycloaddition of 302 with173 afforded triazole 220.

Synthesis of Nitrile 298

A solution of alcohol 285 (5.4 g, 16.1 mmol) in dimethylformamide (16mL) was treated with copper (I) cyanide (1.60 g, 17.7 mmol) and stirredat 145° C. under argon for 18 h. The reaction mixture was cooled to 23°C. and diluted with methylene chloride (100 mL), and washed withsaturated aqueous ammonium chloride (100 mL) and saturated aqueoussodium chloride (100 mL). Drying (Na₂SO₄) and evaporation provided 298(2.9 g, 12.3 mmol, 76%) as a white powder. Data for 298: ¹HNMR (300 MHz,CD₃OD): δ 7.68 (dd, J=12, 2 Hz, 1H), 7.62 (dd, J=9, 8 Hz, 1H), 7.39 (dd,J=9, 2 Hz, 1H), 4.71–4.65 (m, 1H), 4.08–4.02 (m, 1H), 3.86 (dd, J=9, 6Hz, 1H), 3.77 (dd, J=13, 3 Hz, 1H), 3.60 (dd, J=13, 4 Hz, 1H).

Synthesis of Azide 300

A solution of nitrile alcohol 298 (600 mg, 2.50 mmol) in methylenechloride (14 mL) was cooled to 0° C. under argon and treated withtriethylamine (0.70 mL, 5.0 mmol) and methanesulfonyl chloride (0.22 mL,2.8 mmol). The reaction mixture was warmed to 23° C. for 0.5 h andsubsequently diluted with methylene chloride (50 mL), washed with 1 Mhydrochloric acid (15 mL), saturated aqueous sodium bicarbonate (15 mL),and saturated aqueous sodium chloride (15 mL). Drying (Na₂SO₄) andevaporation provided mesylate 299 (0.62 g, 2.0 mmol, 80%) as a whitepowder. Data for 299: ¹HNMR (300 MHz, CDCl₃): δ 7.63 (dd, J=12, 2 Hz,1H), 7.56 (dd, J=9, 7 Hz, 1H), 7.31 (dd, J=9, 2 Hz, 1H), 5.01–4.94 (m,1H), 4.51 (dd, J=12, 3 Hz, 1H), 4.43 (dd, J=12, 4 Hz, 1H), 4.22–4.15 (m,1H), 3.96 (dd, J=9, 6 Hz, 1H), 3.45 (dd, J=15, 7 Hz, 1H), 3.06 (s, 3H).

A solution of mesylate 299 (0.61 g, 1.9 mmol) in dimethylformamide (15mL) was treated with sodium azide (0.26 g, 4.0 mmol) and stirred at 75°C. under argon for 1 h. The reaction mixture was cooled to 23° C.,diluted with water (100 mL) and extracted with methylene chloride (3×50mL). The combined organic layer was washed with water (100 mL). Thesolvent was evaporated and the residue redissolved in ethyl acetate (50mL) and washed with water (100 mL). Drying (Na₂SO₄) and evaporationprovided azide 300 (0.38 g, 1.5 mmol, 79%) as a brown oil. Data for 300:¹HNMR (300 MHz, CDCl₃): δ 7.61–7.52 (m, 2H), 7.28 (dd, J=9, 2 Hz, 1H),4.84–4.76 (m, 1H), 4.084.02 (m, 1H), 3.83 (dd, J=9, 6 Hz, 1H), 3.72 (dd,J=13, 4 Hz, 1H), 3.55 (dd, J=13, 4 Hz, 1H).

Synthesis of Triazole 219

A solution of alkyne 173 (0.15 g, 0.19 mmol) and azide 300 (0.060 g,0.21 mmol) in tetrahydrofuran (1.5 mL) was treated withN,N-diisopropylethylamine (0.066 mL, 0.38 mmol) and copper (I) iodide(19 mg, 0.10 mmol) and stirred under argon at 23° C. for 1 h. Thereaction mixture was diluted with saturated aqueous ammonium hydroxide(10 mL) and extracted with dichloromethane (4×30 mL). The combinedorganic fractions were dried (Na₂SO₄), evaporated, and the residuepurified by flash chromatography (SiO₂, ammoniumhydroxide/methanol/dichloromethane (0.05:1:9) to provide 219 (100 mg,0.095 mmol, 50%) as a white powder. Data for 219: ¹HNMR (300 MHz, CDCl₃,partial): δ 7.62–7.55 (m, 3H), 7.24 (dd, J=9, 2 Hz, 1H), 3.34 (s, 3H),2.32 (s, 3H), 2.24 (s, 3H), 1.02 (d, J=7 Hz, 3H), 0.92–0.80 (m, 6H).

Synthesis of Oxadiazole 301

A solution of nitrile 298 (2.00 g, 8.50 mmol) in methanol (42.5 mL) wastreated with potassium carbonate (1.18 g, 8.50 mmol) and hydroxylaminehydrochloride (1.18 g, 17.0 mmol) and heated to reflux for 18 h. Thereaction mixture was cooled to 23° C., diluted with ethyl acetate (100mL) and washed with water (4×100 mL). Drying (Na₂SO₄) and evaporationafforded a brown powder. A solution of crude this hydroxyamidine (1.00g, 3.7 mmol) in pyridine (17.5 mL) under argon was cooled to 0° C. andtreated dropwise with a solution of acetic anhydride (0.70 mL, 7.4 mmol)in pyridine (17.5 mL). The reaction mixture was heated to 120° C. for 1h and then cooled to 23° C. The reaction mixture was then diluted withethyl acetate (50 mL) and washed with 1 M hydrochloric acid (30 mL),saturated aqueous sodium bicarbonate (30 mL), and saturated aqueoussodium chloride (30 mL) and dried (Na₂SO₄). Flash chromatography (SiO₂,50–75% ethyl acetate/hexanes) afforded the intermediateacetate-protected oxadiazole (0.28 g, 0.84 mmol, 22%) as a white powder.Data for intermediate oxadiazole: MS (ESI) m/z 335.9 (M+H)⁺; ¹HNMR (300MHz, CDCl₃: δ 8.07–8.02 (m, 1H), 7.62 (dd, J=13, 2 Hz, 1H), 7.39 (dd,J=9, 2 Hz, 1H), 4.97–4.89 (m, 1H), 4.41 (dd, J=12, 4 Hz, 1H), 4.33 (dd,J=12, 5 Hz, 1H), 4.21–4.15 (m, 1H), 3.88 (dd, J=9, 6 Hz, 1H), 2.68 (s,3H), 2.11 (s, 3H).

A solution of the oxadiazole acetate obtained above (0.25 g, 0.75 mmol)in methanol (0.75 mL) was treated with sodium methoxide (0.005 mg, 0.08mmol) and stirred at 23° C. for 1 h. The reaction mixture was quenchedwith 1 M hydrochloric acid (0.15 mL) and the solvent was evaporated invacuo to provide oxadiazole 301 (0.21 g, 0.72 mmol, 95%) as a whitepowder. Data for 301: ¹HNMR (300 MHz, CDCl₃): δ 8.06–8.00 (m, 1H), 7.63(dd, J=13, 2 Hz, 1H), 7.39 (dd, J=9, 2 Hz, 1H), 4.81 (m, 1H), 4.07 (m,3H), 3.78 (dd, J=13, 4 Hz, 1H), 2.68 (s, 1H).

Synthesis of Azide 302

A solution of alcohol 301 (0.18 g, 0.61 mmol) in methylene chloride (3.5mL) was cooled to 0° C. under argon and treated with triethylamine (0.18mL, 1.2 mmol) and methanesulfonyl chloride (0.050 mL, 0.68 mmol). Thereaction mixture was warmed to 23° C. for 0.5 h and diluted withmethylene chloride (20 mL), washed with 1 M hydrochloric acid (10 mL),saturated aqueous sodium bicarbonate (10 mL), and saturated aqueoussodium chloride (10 mL). Drying (Na₂SO₄) and evaporation provided theintermediate mesylate (0.19 g, 0.51 mmol, 84%) as a white powder: ¹HNMR(300 MHz, CDCl₃, partial): δ 8.02–7.96 (m, 1H), 7.62–7.45 (m, 1H),4.94–4.87 (m, 1H), 4.46 (dd, J=12, 4 Hz, 1H), 4.39 (dd, J=12, 4 Hz, 1H),4.17–4.11 (m, 1H), 3.95 (dd, J=9, 6 Hz, 1H), 3.05 (s, 3H), 2.61 (s, 3H).

A solution of the above mesylate (0.18 g, 0.49 mmol) indimethylformamide (3.7 mL) was treated with sodium azide (64 mg, 0.98mmol) and stirred at 75° C. under argon for 2 h. The reaction mixturewas cooled to 23° C., poured into H₂O (50 mL), and stirred at 0° C. Theresulting precipitate was filtered, washed with H₂O, and dried underreduced pressure to provide azide 302 (80 mg, 0.25 mmol, 51%) as a whitepowder. Data for 302: ¹HNMR (300 MHz, CDCl₃): δ 8.05 (m, 1H), 7.62 (dd,J=13, 2 Hz, 1H), 7.41–7.39 (m, 1H), 4.88–4.81 (m, 1H), 4.16–4.10 (m,1H), 3.92 (dd, J=9, 6 Hz, 1H), 3.76 (dd, J=13, 5 Hz, 1H), 3.63 (dd,J=13, 4 Hz, 1H), 2.68 (s, 3H).

Synthesis of Triazole 220

A solution of alkyne 173 (0.13 g, 0.16 mmol) and azide 302 (0.060 g,0.19 mmol) in tetrahydrofuran (1.2 mL) was treated withN,N-diisopropylethylamine (0.044 mL, 0.32 mmol) and copper (I) iodide(15 mg, 0.080 mmol) and stirred under argon at 23° C. for 0.5 h. Thereaction mixture was diluted with saturated aqueous ammonium hydroxide(10 mL) and extracted with dichloromethane (4×30 mL). The combinedorganic fractions were dried (Na₂SO₄), evaporated, and the residuepurified by flash chromatography (SiO₂, ammoniumhydroxide/methanol/dichloromethane (0.05:1:9)) to provide 220 (70 mg,0.063 mmol, 40%) as a white powder. Data for 220: MS (ESI) m/z 1105.5(M+H)⁺; ¹NMR (300 MHz, CDCl₃, partial): δ 8.04–7.98 (m, 1H), 7.65 (s,1H), 7.57–7.53 (m, 1H), 7.27–7.24 (m, 1H), 4.81–4.68 (m, 1H), 4.76–4.73(m, 1H), 4.43 (d, J=7 Hz, 1H), 3.35 (s, 3H), 0.99–0.81 (m, 6H).

Example 28 Synthesis of Triazole 221

Scheme 52 details the synthesis of triazole 221. p-Nitrobenzenesulfonylchloride was treated with ammonia to provide sulfonamide 303. The nitrogroup was reduced to provide aniline 304 which was converted tocarbamate 305. Oxazolidinone formation to yield alcohol 306 was followedby standard manipulations to afford azide 308. Cycloaddition of 308 withalkyne 173 yielded triazole 221.

Synthesis of Sulfonamide 303

4-Nitrobenzenesulfonyl chloride (2.22 g, 10 mmol) was added to asolution of concentrated ammonium hydroxide (3 mL) in THF (5 mL) at 0°C. The reaction was stirred at 0° C. for 1 h and then at roomtemperature for additional 1 h. The THF was removed under vaccum, morewater was added, and the precipitate was collected by filtration anddried to afford 303 (1.90 g, 94% yield).

Synthesis of Aniline 304

To a solution of 4-nitrobenzenesulfonamide 303 (1.9 g, 9.4 mmol) inmethanol (20 mL) was added 10% Pd—C (0.19 g) and the resulted mixturewas stirred at room temperature for 12 h under 1 atm hydrogenatmosphere. The Pd—C was removed by filtration on celite. The filteredsolution was evaporated to provide 304 (1.4 g, 87% yield) as a whitesolid. Data for 304: ¹HNMR (300 MHz, CDCl₃-CD₃OD): δ 7.63 (d, J=9 Hz,2H), 6.70 (d, J=9 Hz, 2H).

Synthesis of Carbamate 305

Benzyl chloroformate (1.4 mL, 9.6 mmol) was added dropwise to a solutionof aniline 304 (1.38 g, 8.0 mmol), and NaHCO₃ (2.69 g, 21 mmol) in amixture of THF (5 mL) and water (3 mL) at 0° C. After stirring at sametemperature 2 h, the reaction mixture was diluted with ethyl acetate (30mL). The organic layer was washed with brine (3×50 mL), dried (MgSO₄)and concentrated to provide 2.35 g of white solid 305 in a yield of 96%.Data for 305: ¹HNMR (300 MHz, CD₃OD): δ 7.80 (d, J=9 Hz, 2H), 7.61 (d,J=9 Hz, 2H), 7.43–7.33 (m, 5H), 5.20 (s, 2H).

Synthesis of Alcohol 306

To a solution of carbamate 305 (440 mg, 1.44 mmol) in THF (10 mL) wasadded n-BuLi (2.0 mL, 2.5 M in hexane, 5.03 mmol) at −78° C. and themixture was stirred for 30 min. (R)-(−)-Glycidyl butyrate (0.25 mL, 1.73mmol) was added, the reaction was stirred at −78° C. for 3 h, and thenwarmed to room temperature and stirred overnight. The reaction wascarefully quenched with saturated NH₄Cl and extracted with EtOAc. Theorganic phase was washed with brine, dried (MgSO₄) and concentrated. Theresidue was dissolved in 10 mL of methanol and sodium methoxide (0.2 mL,30% wt/wt in methanol) was added. After stirring at room temperature for2 h, the mixture was concentrated and purified by chromatography(25:1:0.05/CH₂Cl₂:MeOH:NH₃.H₂O) to afford 100 mg of desiredoxazolidinone 306 in a yield of 26%. Data for 306: ¹HNMR (300 MHz,CD₃OD): δ 7.90 (d, J=9 Hz, 2H), 7.78 (d, J=9 Hz, 2H), 4.77 (m, 1H), 4.18(t, J=9 Hz, 1H), 3.99 (dd, J=6, 9 Hz, 1H), 3.87 (dd, J=3, 12 Hz, 1H),3.71 (dd, J=3, 12 Hz, 1H).

Synthesis of Azide 308

To a solution of alcohol 306 (106 mg, 0.39 mmol), Et₃N (129 mg, 1.28mmol) and 4-dimethylaminopyridine (1 mg) in CH₂Cl₂ (10 mL) and DMF (2mL) was added methanesulfonyl chloride (150 mg, 1.31 mmol) at 0° C., andthe mixture was stirred for 2 h. The reaction mixture was concentratedand purified by chromatography on silica gel(10:1:0.05/CH₂Cl₂:MeOH:NH₃.H₂O) to afford mesylate 307 (135 mg, 81%yield). Data for 307: ¹HNMR (300 MHz, CDCl₃): δ 7.85 (d, J=9 Hz, 2H),7.54 (d, J=9 Hz, 2H), 4.96 (m, 1H), 4.50 (dd, J=3, 12 Hz, 1H), 4.42 (dd,J=3, 12 Hz, 1H), 4.16 (t, J=9 Hz, 1H), 3.89 (dd, J=6, 9 Hz, 1H), 2.90(s, 3H), 2.80 (s, 3H).

A mixture of 307 (135 mg, 0.30 mmol) and sodium azide (101 mg, 1.56mmol) in DMF (1 mL) was heated at 80° C. for 2 h. The reaction mixturewas diluted with CH₂Cl₂ (10 mL), filtered, concentrated and purified byflash chromatography to afford crude azide 308 (118 mg), which was ofsufficient purity to be used in subsequent reactions. Data for 308:¹HNMR (300 MHz, CDCl₃-CD₃OD): δ 7.73 (d, J=8 Hz, 2H), 7.43 (d, J=8 Hz,2H), 4.67 (m, 1H), 3.97 (t, J=9 Hz, 1H), 3.71 (dd, J=7, 8 Hz, 1H), 3.57(dd, J=3, 13 Hz, 1H), 3.41 (dd, J=4, 13 Hz, 1H), 2.76 (s, 3H).

Synthesis of Triazole 221

A mixture of alkyne 173 (118 mg, 0.15 mmol), azide 308 (118 mg, preparedas above) and copper (I) iodide (28.5 mg, 0.15 mmol) in THF (5 mL) wasrepeatedly degassed and flushed with argon. i-Pr₂NEt (0.26 mL) wasintroduced and the mixture was stirred at room temperature for 2 h. Thereaction mixture was poured into saturated NH₄Cl (30 mL) and stirred for15 minutes. The mixture was extracted with CH₂Cl₂, washed with brine,dried over MgSO₄ and concentrated. The crude material waschromatographed on silica gel (10:1:0.05 CH₂Cl₂/MeOH/NH₃.H₂O) to providetriazole 221 (108 mg, 62% yield) as a white foam. Data for 221: MS (ESI)m/z 1162.3 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃-DMSO, partial): δ 7.91 (d, J=9Hz, 2H), 7.85 (s, 1H), 7.51 (d, J=9 Hz, 2H), 3.35 (s, 3H), 3.33 (s, 3H),3.32 (s, 3H), 0.89 (t, J=8 Hz, 3H).

Example 29 Synthesis of Triazole 222

Scheme 53 details the synthesis of triazole 222. Sulfonamide 309 wasprotected as the sulfonamidine 310 prior to conversion to oxazolidinonealcohol 311. Alcohol 311 was transformed to azide 314 via functionalgroup interconversion followed by hydrolysis of the amidine protectinggroup. Cycloaddition of 314 with alkyne 173 provided triazole 222.

Synthesis of Sulfonamidine 310

A solution of sulfonamide 309 (1.10 g, 3.59 mmol, prepared from3-nitrobenzenesulfonyl chloride by using similar procedures describedfor the preparation of 305), thionyl chloride (1.30 mL, 17.97 mmol) andDMF (5 mL) in CH₂Cl₂ (20 mL) was refluxed for 0.5 h. The reaction wascooled with an ice-bath and neutralized with saturated NaHCO₃. Theorganic phase was separated, washed with brine, dried over MgSO₄ andevaporated to provide 310 as a white solid (1.25 g, 96% yield). Data for310: ¹HNMR (300 MHz, CDCl₃): δ 8.12 (s, 1H), 7.81 (t, J=4 Hz, 1H), 7.74(m, 1H), 7.59 (m, 1H), 7.44–7.35 (m, 6H), 6.98 (br s, 1H), 5.22 (s, 2H),3.12 (s, 3H), 3.02 (s, 3H).

Synthesis of Alcohol 311

To a solution of 310 (724 mg, 2.0 mmol) in THF (16 mL) was added n-BuLi(1.5 mL, 2.5 M in hexane, 3.5 mmol) at −78° C. and the mixture wasstirred for 30 min. (R)-(−)-Glycidyl butyrate (0.35 mL, 2.5 mmol) wasadded, the reaction was stirred at −78° C. for 3 h, and then warmed toroom temperature and stirred overnight. The reaction was carefullyquenched with saturated NH₄Cl and extracted with EtOAc. The organicphase was washed with brine, dried (MgSO₄) and concentrated. The residuewas dissolved in 10 mL of methanol and sodium methoxide (0.2 mL, 30%wt/wt in methanol) was added. After stirring at room temperature for 2h, the mixture was concentrated and purified by chromatography on silicagel (25:1:0.05/CH₂Cl₂:MeOH:NH₃.H₂O) to afford 311 as a white solid (350mg, 53% yield). Data for 311: ¹HNMR (300 MHz, CDCl₃): δ 8.06 (s, 1H),7.87 (dd, J=2, 8 Hz, 1H), 7.79 (t, J=2 Hz, 1H), 7.57 (m, 1H), 7.39 (t,J=8 Hz, 1H), 4.70 (m, 1H), 3.99 (m, 2H), 3.92 (dd, J=3, 12 Hz, 1H), 3.70(dd, J=4, 12 Hz, 1H), 3.08 (s, 3H), 2.96 (s, 3H).

Synthesis of Azide 314

To a solution of alcohol 311 (170 mg, 0.52 mmol) and Et₃N (58 mg, 0.57mmol) in CH₂Cl₂ (10 mL) was added methanesulfonyl chloride (72 mg, 0.62mmol) at 0° C. and the mixture was stirred for 30 min. The CH₂Cl₂solution was washed with brine, dried (MgSO₄) and concentrated to affordmesylate 312 (200 mg, 95% yield). Data for 312: ¹HNMR (300 MHz, CDCl₃):δ 8.05 (s, 1H), 7.79 (m, 2H), 7.56 (d, J=8 Hz, 1H), 7.39 (t, J=8 Hz,1H), 4.90 (m, 1H), 4.45 (dd, J=4, 12 Hz, 1H), 4.37 (dd, J=4, 12 Hz, 1H),4.14 (t, J=9 Hz, 1H), 3.91 (dd, J=6, 9 Hz, 1H), 3.08 (s, 3H), 3.03 (s,3H), 2.95 (s, 3H).

A mixture of mesylate 312 (105 mg, 0.26 mmol) and sodium azide (67 mg,1.04 mmol) in DMF (2 mL) was heated at 80° C. for 2 h. The reaction wasthen diluted with ethyl acetate, washed with brine, dried (MgSO₄) andevaporated to provide azide 313 as a white solid (80 mg, 87% yield).Data for 313: ¹HNMR (300 MHz, CDCl₃): δ 8.06 (s, 1H), 7.84 (m, 1H), 7.78(t, J=2 Hz, 1H), 7.56 (d, J=8 Hz, 1H), 7.40 (t, J=8 Hz, 1H), 4.77 (m,1H), 4.07 (t, J=9 Hz, 1H), 3.84 (dd, J=6, 9 Hz, 1H), 3.67 (dd, J=4, 13Hz, 1H), 3.53 (dd, J=4, 13 Hz, 1H), 3.08 (s, 3H), 2.95 (s, 3H).

To a solution of azide 313 (80 mg, 0.23 mmol) in methanol (5 mL) wasadded concentrated HCl (0.5 mL). After refluxing for 4 h, the reactionwas cooled with an ice-bath and neutralized with saturated NaHCO₃. Theresulting mixture was extracted with CH₂Cl₂, washed with brine, driedover MgSO₄ and evaporated to provide 314 (58 mg, 86% yield). Data for314: ¹HNMR (300 MHz, CDCl₃-CD₃OD): δ 7.86 (m, 1H), 7.68 (d, J=8 Hz, 1H),7.55 (d, J=8 Hz, 1H), 7.39 (t, J=8 Hz, 1H), 4.75 (m, 1H), 4.04 (t, J=9Hz, 1H), 3.80 (dd, J=6, 9 Hz, 1H), 3.64 (dd, J=4, 13 Hz, 1H), 3.47 (dd,J=4, 13 Hz, 1H).

Synthesis of Triazole 222

To a solution of alkyne 173 (79 mg mg, 0.10 mmol), azide 314 (36 mg,0.12 mmol) and copper (I) iodide (38 mg, 0.2 mmol) in THF (5 mL) underargon was added i-Pr₂NEt (0.18 mL). After stirring at room temperaturefor 2 h, the reaction mixture was poured into saturated NH₄Cl (30 mL)and stirred for 15 minutes. The mixture was extracted with CH₂Cl₂,washed with brine, dried over MgSO₄ and concentrated. The crude materialwas chromatographed on silica (10:1 CH₂Cl₂/MeOH) to provide triazole 222(65 mg, 60% yield) as a white foam. Data for 222: MS (ESI) m/z 1084.4(M+H)⁺; ¹HNMR (300 MHz, CDCl₃-DMSO, partial): δ 7.76 (s, 1H), 7.71 (d,J=8 Hz, 1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.36 (t, J=8 Hz, H), 0.81 (t,J=7 Hz, 3H).

Example 30 Synthesis of Triazoles 223 and 224

Scheme 54 details the synthesis of triazoles 223 and 224. Sulfonamide305 was protected as sulfonamidine 315 prior to conversion tooxazolidinone alcohol 316. Transformation of 316 to azide 319 asdescribed previously was followed by cycloaddition of 319 with alkyne173 to produce triazole 223. The cycloaddition of intermediate azide 318with alkyne 173 afforded triazole 224.

Synthesis of Sulfonamidine 315

Sulfonamidine 315 was synthesized using the same procedure described forthe preparation of 310; 0.92 g of 305 afforded 1.02 g of 315 (94%yield). Data for 315: ¹HNMR (300 MHz, CDCl₃): δ 8.10 (s, 1H), 7.81 (d,J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 7.41–7.34 (m, 5H), 6.89 (br s, 1H),5.20 (s, 2H), 3.11 (s, 3H), 3.00 (s, 3H).

Synthesis of Alcohol 316

Alcohol 316 was synthesized using the same procedure described for thepreparation of 311; 0.97 g of 315 afforded 0.60 g of 316 (69% yield).Data for 316: ¹HNMR (300 MHz, CDCl₃-CD₃OD): δ 8.03 (s, 1H), 7.79 (d, J=9Hz, 2H), 7.59 (d, J=9 Hz, 2H), 4.68 (m, 1H), 3.98 (m, 2H), 3.84 (dd,J=4, 13 Hz, 1H), 3.64 (dd, J=4, 13 Hz, 1H), 3.08 (s, 3H), 2.95 (s, 3H).

Synthesis of Azide 318

Mesylate 317 was synthesized using the same procedure described for thepreparation of 312; 176 mg of 316 afforded 210 mg of 317 (96% yield).Data for 317: ¹HNMR (300 MHz, CDCl₃): δ 8.06 (s, 1H), 7.83 (d, J=9 Hz,2H), 7.57 (d, J=9 Hz, 2H), 4.90 (m, 1H), 4.41 (m, 2H), 4.13 (t, J=9 Hz,1H), 3.94 (dd, J=6, 9 Hz, 1H), 3.10 (s, 3H), 3.06 (s, 3H), 2.95 (s, 3H).

Azide 318 was synthesized using the same procedure described for thepreparation of 313; 210 mg of 317 afforded 180 mg of 318 (98% yield).Data for 318: ¹HNMR (300 MHz, CDCl₃): δ 8.04 (s, 1H), 7.82 (d, J=9 Hz,2H), 7.60 (d, J=9 Hz, 2H), 4.90 (m, 1H), 4.08 (t, J=9 Hz, 1H), 3.85 (dd,J=6, 9 Hz, 1H), 3.70 (dd, J=4, 13 Hz, 1H), 3.55 (dd, J=4, 13 Hz, 1H),3.09 (s, 3H), 2.96 (s, 3H).

Synthesis of Azide 319

Azide 319 was synthesized using the same procedure described for thepreparation of 314; 150 mg of 318 afforded 118 mg of 319 (93% yield).Data for 319: ¹HNMR (300 MHz, CDCl₃-CD₃OD): δ 7.78 (d, J=9 Hz, 2H), 7.56(d, J=9 Hz, 2H), 4.74 (m, 1H), 4.04 (t, J=9 Hz, 1H), 3.80 (dd, J=6, 9Hz, 1H), 3.64 (dd, J=4, 13 Hz, 1H), 3.48 (dd, J=4, 13 Hz, 1H).

Synthesis of Triazole 223

Triazole 223 was synthesized using the same procedure described for thepreparation of 222; the reaction of alkyne 173 (118 mg, 0.15 mmol) andazide 319 (54 mg, 0.18 mmol) afforded 150 mg of 223 (92% yield). Datafor 223: MS (ESI) m/z 1084.4 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ7.77 (d, J=9 Hz, 2H), 7.55 (s, 1H), 7.45 (d, J=9 Hz, 2H), 3.26 (s, 3H),0.82 (t, J=8 Hz, 3H).

Synthesis of Triazole 224

Triazole 224 was synthesized using the same procedure described for thepreparation of 222; the reaction of alkyne 173 (79 mg, 0.10 mmol) andazide 318 (43 mg, 0.12 mmol) afforded 93 mg of 224 (82% yield). Data for224: MS (ESI) m/z 1139.7 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.04(s, 1H), 7.78 (d, J=9 Hz, 2H), 7.54 (s, 1H), 7.45 (d, J=9 Hz, 2H), 3.27(s, 3H), 3.07 (s, 3H), 2.94 (s, 3H), 0.82 (t, J=8 Hz, 3H).

Example 31 Synthesis of Triazoles 225–227

Scheme 55 details the synthesis of triazole 225. 3,4-Dichloroaniline wasconverted to carbamate 320 before being carried further through alcohol321 to azide 323. The cycloaddition of 323 with alkyne 173 gave triazole225. Triazoles 226 and 227 were synthesized from the requisite anilinesusing the same sequence as described in Scheme 55.

Synthesis of Carbamate 320

Sodium bicarbonate (2.60 g, 24.7 mmol) was dissolved in water (22 mL)and 3,4-dichloroaniline (2.0 g, 12.34 mmol) was added. The mixture wascooled to 0° C., and benzyl chloroformate (1.76 mL, 12.34 mmol) wasadded. The mixture was stirred 5 min at 0° C., the cold bath removed,and then stirring was continued at room temperature overnight (˜16hours). The mixture was evaporated, and partitioned with a 1:1 mixtureof ethyl acetate and water. The organic layer was washed with water, andthen brine. The organic layer was dried with Na₂SO₄, and evaporated toyield 320 (3.60 g, 99% yield) of suitable purity for use in subsequentreactions. Data for 320: ¹HNMR (300 MHz, CDCl₃): δ 7.18–7.14 (m, 5H),7.42 (s, 1H), 6.98 (dd, J=11, 3 Hz, 1H), 6.48 (s, 1H), 5.06 (s, 2H).

Synthesis of Alcohol 321

Carbamate 320 (3.60 g, 12.16 mmol) was dissolved in 10 mLtetrahydrofuran, and the solution cooled to −78° C. n-Butyllithium (2.5M in hexane, 7.6 mL, 12.16 mmol) was added slowly, and the mixtureallowed to stir for 45 min at −78° C. R-(−)-Glycidyl butyrate (1.75 mL,12.16 mmol) was added, and the mixture was stirred for 1 h at −78° C.The bath was removed and the reaction allowed to stir overnight at roomtemperature. The reaction was quenched with 25 mL saturated ammoniumchloride solution, and partitioned with ethyl acetate and water. Theaqueous layer was extracted thrice with ethyl acetate, and the combinedorganic layer was washed with brine, dried (Na₂SO₄), and evaporated toyield 321 (2.80 g, 88% yield) of suitable purity for use in subsequentreactions. Data for 321: ¹HNMR (300 MHz, CDCl₃): δ 7.59 (s, 1H), 7.33(s, 1H), 4.68 (m, 1H), 3.91 (m, 3H), 3.67 (dd, J=16, 4 Hz, 1H).

Synthesis of Azide 323

Alcohol 321 (2.80 g, 10.68 mmol) was dissolved in 10 mL methylenechloride, and the mixture cooled to 0° C. Triethylamine (3.0 mL, 21.37mmol) was added, followed by methanesulfonyl chloride (1.15 mL, 15.0mmol). The mixture was allowed to warm to room temperature and stirredfor 1 h. Methylene chloride (20 mL) was added, and the mixture washedtwice with 1N HCl, then twice with 10% aqueous sodium carbonate, andthen brine. The organic phase was dried (Na₂SO₄), and evaporated toyield mesylate 322 (3.60 g, 99% yield). Data for 322: ¹HNMR (300 MHz,CDCl₃): δ 7.67 (s, 1H), 7.42 (s, 2H), 4.94 (m, 1H), 4.47 (m, 2H), 4.26(m, 1H), 4.0 (m, 1H), 3.03 (s, 3H).

A solution of mesylate 322 (3.60 g, 10.58 mmol) in dimethylformamide (10mL) was treated with sodium azide (2.6 g, 40.21 mmol) and the mixtureheated to 80° C. for 5 h. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate (100 mL), and washed with brine(2×50 mL). Drying (Na₂SO₄), and evaporation provided azide 323 (2.53 g,84% yield) as a yellow solid of suitable purity for use in subsequentreactions. Data for 323: ¹HNMR (300 MHz, CDCl₃): δ 7.61 (s, 1H), 7.30(s, 2H), 4.75 (m, 1H), 4.01 (m, 1H), 3.75 (m, 1H), 3.66 (dd, J=17, 4 Hz,1H), 3.51 (dd, J=4, 17 Hz, 1H).

Synthesis of Triazole 225

A solution of alkyne 173 (170 mg, 0.220 mmol) in tetrahydrofuran (10 mL)was treated with azide 323 (100 mg, 0.320 mmol),N,N-diisopropylethylamine (0.05 mL, 0.22 mmol) and copper (I) iodide(0.03 g, 0.160 mmol), and the mixture was stirred under argon at roomtemperature for 16 h. The reaction mixture was diluted with ethylacetate (50 mL), and washed with brine (2×50 mL). The organic phase wasdried and evaporated. The residue was purified by preparative thin layerchromatography using (80% CH₂Cl₂, 20% MeOH, 1% NH₄OH) to providetriazole 225 (180 mg, 77% yield) as a white solid. Data for 225: MS(ESI) m/z 1075 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.95 (s, 1H),7.46 (s, 1H), 7.20 (d, J=8 Hz, 1H), 7.04 (s, 2H), 5.04–4.93 (m, 1H),4.91 (s, 2H), 4.28 (d, J=6 Hz, 1H), 3.98–3.92 (m, 2H), 3.61 (s, 1H),3.59–3.48 (m, 1H), 3.34 (s, 1H), 3.19 (s, 1H), 3.06 (m, 1H), 2.94 (m,1H).

Synthesis of Triazoles 226 and 227

These compounds were synthesized from the requisite anilines using theprocedures described above for the synthesis of triazole 225.

Data for 226: ¹H-NMR (300 MHz, CDCl₃, partial): δ 8.01 (s, 1H), 7.60 (s,1H), 7.02 (m, 1H), 6.77 (m, 1H), 4.98–4.68 (m, 1H), 4.37 (s, 2H),4.13–4.04 (m, 2H), 3.89 (m, 1H), 3.26 (s, 1H), 2.84 (m, 2H), 2.66 (m,2H).

Data for 227: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.50 (s, 1H), 7.00 (s,1H), 6.82 (d, J=9 Hz, 1H), 6.64 (d, J=9 Hz, 1H), 5.02–4.89 (s, 1H), 4.53(m, 2H), 4.34 (m, 2H), 3.19 (m, 1H), 2.96 (m, 1H), 2.93 (m, 2H), 2.86(m, 2H).

Example 32 Synthesis of Triazole 228

Scheme 56 details the synthesis of triazole 228. 5-Aminoquinoline wasconverted to oxazolidinone alcohol 325 via carbamate 324. The alcohol of325 was the transformed to azide 326, which was parlayed to triazole 228via cycloaddition with alkyne 173.

Synthesis of Azide 326

To a stirred 0° C. solution of 5-aminoquinoline (1.0 g, 6.9 mmol) in 2:1acetone/water (15 mL) was added NaHCO₃ (1.0 g, 13.7 mmol) followed bybenzyl chloroformate (1.1 mL, 7.7 mmol). The reaction mixture wasallowed to warm to room temperature and stirred for 2h then cooled to 0°C. and filtered. The filtrate was washed with water and ether and driedin a vacuum oven at 40° C. overnight. The yellow solid (carbamate 324)thus obtained (1.9 g, 100% yield) was used as-is without furtherpurification.

To a mixture of 324 (1.9 g, 6.9 mmol) in 25 mL THF at −78° C. was added4.3 mL (6.9 mmol) of 1.6M n-butyllithium-hexane over 5 minutes. After 30minutes, 1 mL of (R)-glycidyl butyrate was added and the mixture allowedto stir at −78° C. for 1 hour and then at room temperature for 16 hr.Saturated ammonium chloride was added (25 mL) followed by ethyl acetate(100 mL). The layers were separated and the aqueous layer extracted withethyl acetate (3×50 mL). The combined organic extracts were dried onMgSO₄, filtered and concentrated to provide 2.3 g of yellow solid whichwas purified by silica gel chromatography (50 mm×6″ column, eluted with1:1 hexane/EtOAc to afford alcohol 325 as a yellow solid (450 mg, 27%yield).

To a stirred solution of 325 (300 mg, 1.2 mmol) in DMF (5 mL) was addedtriethylamine (0.34 mL, 2.4 mmol) followed by methanesulfonyl chloride(95 μL, 1.2 mmol). The mixture was stirred at room temperature and for2h, and then sodium azide (1 g, 15 mmol) was added and the slurrystirred overnight. The mixture was diluted with water (100 mL) andextracted with ethyl acetate (3×50 mL). The combined organic extractswere washed with brine, dried (Na₂SO₄), filtered and concentrated togive 287 mg of azide 326 as an off-white solid which was used withoutfurther purification.

Synthesis of Triazole 228

To a stirred solution of alkyne 173 (50 mg, 64 μmol) in THF (250 μL) wasadded azide 326 (18 mg, 67 μmol) and cuprous iodide (5 mg, 26 μmol). Theresulting mixture was degassed by alternately applying vacuum andpurging with argon gas. The mixture was stirred under argon at ambienttemperature for 16 h. The entire reaction mixture was then placed atop asilica gel flash chromatography column and eluted with 100:3 CH₂Cl₂/2NNH₃ in MeOH to afford the desired triazole adduct 228 as a white solid(50 mg, 74% yield). Data for 228: MS (ESI) m/z 322.9 (M+3H)³⁺, 528.6(M+2H)²⁺, 1056.4 (M+H)⁺, 1078.3 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃,partial): δ 9.05 (d, J=3 Hz, 1H), 8.05 (m, 2H), 7.90 (bs, 1H), 7.71 (dd,J=8, 3 Hz, 1H), 7.48 (s, 1H), 7.50 (d, J=7.0 Hz, 1H), 5.18–5.01 (m, 1H),4.95 (d, J=5 Hz, 1H), 4.75 (d, J=4 Hz, 2H), 4.58 (dd, J=10, 2 Hz, 1H),4.38 (d, J=7 Hz, 1H), 4.25 (t, J=9 Hz, 1H), 4.06 (dd, J=9, 6 Hz, 1H),4.08–3.92 (m, 1H), 3.79 (d, J=7 Hz, 1H), 3.26 (s, 3H), 3.15 (dd, J=10, 7Hz, 1H), 2.95 (t, J=10 Hz, 1H), 2.28 (s, 3H), 2.20 (s, 3H), 0.82 (m,6H).

Example 33 Synthesis of Triazoles 229–232

Scheme 57 details the synthesis of targets 229–232. Hex-5-yn-1-ol wasconverted to tosylate 327 which served as an alkylating agent for amine171. Acetylene 328 was the precursor for cycloaddition reactions withazides 326, 158, 189, and 188 to yield triazoles 229, 230, 231, and 232respectively.

Synthesis of Tosylate 327

To a stirred, ice-cold solution of hex-5-yn-1-ol (1.0 g, 10.2 mmol) inether (20 mL) was added p-toluenesulfonyl chloride (2.14 g, 11.2 mmol).Powdered KOH (1.1 g, 20.4 mmol) was then added portion-wise over 5minutes. The slurry was stirred at 0° C. for 3 hours then poured into100 mL water, and extracted with ether (2×50 mL). The combined organicextracts were washed with brine, dried over MgSO₄, filtered, andconcentrated to afford 327 as a colorless oil (2.3 g, 89% yield). Datafor 327: ¹HNMR (300 MHz, CDCl₃): δ 7.80 (d, J=8 Hz, 2H), 7.35 (d, J=8Hz, 2H), 4.05 (t, J=6 Hz, 2H) 2.45 (s, 3H), 2.19 (td, J=7, 3 Hz, 2H),1.79 (pent, J=7 Hz, 2H), 1.55 (pent., J=7 Hz, 2H); ¹³C NMR (75 MHz,CDCl₃): δ 144.8, 133.0, 129.9, 127.9, 83.4, 69.9, 69.0, 27.7, 24.2,21.6, 17.7.

Synthesis of Alkyne 328

A 20 mL vial was charged with tosylate 327 (0.20 g, 0.85 mmol),N-desmethyl azithromycin 171 (0.5 g, 0.68 mmol), and Hunig's base (10mL), and then purged with argon gas and sealed. The solution was stirredin a 100° C. oil bath for 6 h. After cooling to room temperature, thereaction mixture was poured into saturated aqueous NaHCO₃ (50 mL) andextracted with CH₂Cl₂ (3×50 mL). The combined organic extracts werewashed with brine, dried over K₂CO₃, filtered, and concentrated toafford 0.8 g of a white solid. Purification by silica gel flashchromatography (25 mm×6″ column eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH)gave 328 as a white solid (0.38 g, 68% yield). Data for 328: MS (ESI)m/z 408.0 (M+2H)²⁺, 815.3 (M+H)⁺.

Synthesis of Triazole 229

To a stirred solution of alkyne 328 (50 mg, 63 μmol) in THF (250 μL) wasadded azide 326 (18 mg, 67 μmol) and cuprous iodide (5 mg, 26 μmol). Theresulting mixture was degassed by alternately applying vacuum andpurging with argon gas. The mixture was stirred under argon at ambienttemperature for 16 h. The entire reaction mixture was then placed atop asilica gel flash chromatography column and eluted with 100:3 CH₂Cl₂/2NNH₃ in MeOH to afford the desired triazole adduct 229 as a white solid(54 mg, 76% yield). Data for 229: MS (ESI) m/z 332.2 (M+3H)³⁺, 542.5(M+2H)²⁺, 1070.3 (M+H)⁺1092.2 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 9.10 (d, J=3 Hz, 1H), 8.05 (m, 2H), 8 (bs, 1H), 7.72 (dd, J=8, 3 Hz,1H), 7.48 (s, 1H), 7.50 (d, J=7 Hz, 1H), 5.20–5.03 (m, 1H), 4.95 (d, J=5Hz, 1H), 4.75 (d, J=4 Hz, 2H), 4.58 (dd, J=10, 2 Hz, 1H), 4.36 (d, J=7Hz, 1H), 4.23 (t, J=9 Hz, 1H), 4.07 (dd, J=9, 6 Hz, 1H), 4.08–3.94 (m,1H), 3.79 (d, J=7 Hz, 1H), 3.24 (s, 3H), 3.15 (dd, J=10, 7 Hz, 1H), 2.95(t, J=10 Hz, 1H), 2.28 (s, 3H), 2.20 (s, 3H), 0.83 (m, 6H).

Synthesis of Triazole 230

To a stirred solution of 328 (35 mg, 43 μmol) in THF (150 μL) was addedHunig's base (30 μL), azide 158 (28 mg, 86 μmol), and cuprous iodide (4mg, 21 μmol). The mixture was degassed by alternately applying vacuumand purging with argon gas. The slurry was stirred under argon atambient temperature for 4 h. The entire reaction mixture was then placedatop a silica gel flash chromatography column and eluted with 50:1CH₂Cl₂/2N NH₃ in MeOH to afford triazole 230 as a white solid (24 mg,50% yield). Data for 230: MS (ESI) m/z 568.8 (M+2H)²⁺, 1136.4 (M+H)⁺;¹HNMR (300 MHz, CDCl₃, partial): δ 8.45 (bs, 1H), 7.55 (s, 1H), 7.33(dd, J=14, 2 Hz, 1H), 6.98 (dd, J=9, 2 Hz, 1H), 6.90 (dd, J=14, 9 Hz,1H), 5.10–4.95 (m, 2H), 4.80–4.60 (m, 2H), 4.50 (d, J=7 Hz 1H), 3.32 (s,3H), 2.32 (bs, 3H), 2.22 (bs, 3H), 0.90 (m, 6H).

Synthesis of Triazole 231

To a stirred solution of 328 (35 mg, 43 μmol) in THF (150 μL) was addedHunig's base (30 μL), azide 189 (20 mg, 86 μmol) and cuprous iodide (4mg, 22 μmol). The resulting slurry was degassed by alternately applyingvacuum and purging with argon gas. The mixture was stirred under argonat ambient temperature for 4 h. The entire reaction mixture was thenplaced atop a silica get flash chromatography column and eluted with50:1 CH₂Cl₂/2N NH₃ in MeOH to afford the triazole adduct 231 as a whitesolid (31 mg, 70% yield). Data for 231: MS (ESI) m/z 526.4 (M+2H)²⁺,1073.5 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.6 (bs, 1H), 7.55(s, 1H), 7.4–7.2 (m, 2H), 7.08 (dd, J=8, 2 Hz, 1H), 6.78 (td, J=6, 2 Hz,2H), 5.1–5.0 (m, 2H), 4.8–4.6 (m, 3H), 4.4 (d, J=7 Hz, 1H), 3.95 (dd,J=9, 6 Hz, 1H), 3.31 (s, 3H), 2.32 (bs, 3H), 2.25 (s, 3H), 0.82 (m, 6H).

Synthesis of Triazole 232

To a stirred solution of 328 (50 mg, 62 μmol) in THF (150 μL) was addedazide 188 (18 mg, 65 μmol) and cuprous iodide (5 mg, 26 μmol). Theresulting mixture was degassed by alternately applying vacuum andpurging with argon gas. The mixture was stirred under argon at ambienttemperature for 16 h. The entire reaction mixture was then placed atop asilica gel flash chromatography column and eluted with 50:1 CH₂Cl₂/2NNH₃ in MeOH to afford the desired triazole adduct 232 as a white solid(54 mg, 81% yield). Data for 232: MS (ESI) m/z 538.4 (M+2H)²⁺, 1075.4(M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.87 (dd, J=7, 2 Hz, 2H),7.70 (bs, 1H), 7.45 (dd, J=9, 2 Hz, 2H), 4.90 (d, J=4 Hz, 1H), 4.75–4.60(m, 2H), 4.58 (d, J=9 Hz, 1H), 4.39 (d, J=7 Hz, 1H), 4.20 (d, J=5 Hz,1H), 4.18 (t, J=9 Hz, 1H), 4.10–3.90 (m, 1H), 3.92 (dd, J=10, 6 Hz, 1H),3.32 (s, 3H), 3.15 (dd, J=10, 7 Hz, 1H), 2.95 (t, J=10 Hz, 1H), 2.28 (s,3H), 2.20 (s, 3H), 0.82 (m, 6H).

Example 34 Synthesis of Triazoles 233 and 234

Synthesis of Triazole 233

Compound 180 (50 mg, 49 μmol) was dissolved in EtOH (1.6 mL), and 1N HCl(aq) was then added (0.4 mL) and the solution stirred at roomtemperature for 12 h. The reaction mixture was diluted with 10 mL aq.0.2N HCl and washed with CH₂Cl₂ (3×10 mL). The aqueous layer was thenadjusted to pH 10 by addition of 2N KOH and extracted with CH₂Cl₂ (2×10mL). The latter two extracts were dried on K₂CO₃, filtered andconcentrated to afford 233 as a solid (37 mg, 87% yield). Data for 233:MS (ESI) m/z 433.4 (M+2H)²⁺, 865.3 (M+H)⁺, 887.3 (M+Na)⁺; ¹HNMR (300MHz, CDCl₃, partial): δ 7.59 (s, 1H), 7.35–7.20 (m, 2H), 7.05 (dd, J=8,2 Hz, 1H), 6.78 (td, J=8, 2 Hz, 2H), 4.98 (m, 1H), 4.75–4.60 (m, 3H),4.35 (d, J=7 Hz, 1H), 4.15–3.98 (m, 2H), 3.88 (dd, J=9, 6 Hz, 1H), 3.7(dd, J=10, 4 Hz, 1H), 2.31 (bs, 3H), 2.10 (s, 3H), 0.82 (m, 6H).

Synthesis of Triazole 234

Compound 231 (10 mg, 8.8 μmol) was dissolved in EtOH (0.8 mL), and 1NHCl (aq) was then added (0.2 mL) and the solution stirred at roomtemperature for 12 h. The reaction mixture was diluted with 10 mL aq.0.2N HCl and washed with CH₂Cl₂ (3×10 mL). The aqueous layer was thenadjusted to pH 10 by addition of 2N KOH and extracted with CH₂Cl₂ (2×10mL). The latter two extracts were dried on K₂CO₃, filtered, andconcentrated to afford 234 as a solid (7 mg, 89% yield). Data for 234:MS (ESI) m/z 447.2 (M+2H)²⁺, 893.5 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃,partial): δ 7.59 (s, 1H) 7.35–7.20 (m, 2H), 7.00 (dd, J=8, 2 Hz, 1H),6.78 (td, J=8, 2 Hz, 2H), 5.05–4.95 (m, 1H), 4.75–4.60 (m, 3H), 4.40 (d,J=7 Hz 1H), 4.15–3.98 (m, 2H), 3.88 (dd, J=9, 6 Hz, 1H), 3.70 (dd,J=10.4, 4.43 Hz, 1H), 2.31 (bs, 3H), 2.10 (s, 3H), 0.82 (m, 6H).

Example 35 Synthesis of Triazoles 235 and 236

Scheme 58 illustrates the synthesis of triazoles 235 and 236.2-Penten-4-yn-1-ol was converted to tosylate 329 which was used toalkylate amine 171 to yield enyne 330. The cycloaddition of alkyne 330with azide 158 and 189 gave triazole products 235 and 236 respectively.

Synthesis of Tosylate 329

To a stirred ice-cold solution of 2-penten-4-yn-1-ol (0.821 g, 10 mmol)in ether (25 mL) was added p-toluenesulfonyl chloride (2.0 g, 10.5mmol). Powdered KOH (1.0 g, 17.8 mmol) was then added portionwise over 5minutes. The slurry was stirred at 0° C. for 45 minutes. The reactionmixture was poured into 100 mL water, and extracted with ether (2×50mL). The combined organic extracts were washed with brine, dried overMgSO₄, filtered, and concentrated to afford 329 as a yellow oil (2.1 g,89% yield). Data for 329: ¹HNMR (300 MHz, CDCl₃): δ 7.80 (d, J=8 Hz,2H), 7.35 (d, J=8 Hz, 2H), 6.12 (dt, J=16, 6 Hz, 1H), 5.70 (ddd, J=16,2, 2 Hz, 1H), 4.60–4.50 (m, 2H), 2.95 (d, J=2, Hz 1H), 2.45 (s, 3H); ¹³CNMR (75 MHz, CDCl₃): δ 145.1, 135.9, 132.9, 130.0, 127.9, 113.9, 80.3,79.8, 69.0, 21.66.

Synthesis of Enyne 330

A 20 mL vial was charged with tosylate 329 (0.20 g, 0.85 mmol),N-desmethyl azithromycin 171 (0.5 g, 0.68 mmol), and Hunig's base (10mL) then purged with argon gas and sealed. The solution was stirred in a100° C. oil bath for 1 h. After cooling to room temperature, thereaction mixture was poured into saturated aqueous NaHCO₃ (50 mL) andextracted with CH₂Cl₂ (3×50 mL). The combined organic extracts werewashed with brine, dried over K₂CO₃, filtered, and concentrated toafford 0.72 g of a viscous yellow oil. Purification by silica gel flashchromatography (25 mm×6″ column eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH)gave 330 as a yellow solid (0.48 g, 88% yield). Data for 330: MS (ESI)m/z 400.2 (M+2H)²+, 799.3 (M+H)⁺, 821.2 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃,partial): δ 8.00 (bs, 1H), 6.20 (dt, J=16, 7, Hz, 1H), 5.70–5.60 (m,1H), 5.00 (d, J=4 Hz, 1H), 4.65 (m, 1H), 4.48 (d, J=7 Hz, 1H), 4.28 (dd,J=6, 2 Hz, 1H), 4.15–3.99 (m, 1H), 3.82 (d, J=6 Hz, 1H), 3.65 (d, J=7Hz, 1H), 3.60–3.40 (m, 1H), 3.32 (s, 3H), 3.32–3.20 (m, 2H), 2.32 (s,3H), 2.26 (s, 3H), 0.86 (m, 6H); ¹³C NMR (75 MHz, CDCl₃): δ 179.3,144.4, 111.8, 103.8, 96.2, 85.1, 82.6, 79.7, 79.0, 78.5, 77.5, 75.7,75.3, 74.4, 73.8, 71.9, 71.0, 69.4, 66.5, 65.4, 62.9, 57.0, 50.39, 45.9,43.4, 42.0, 37.6, 37.5, 35.9, 31.8, 31.2, 28.2, 27.7, 22.8, 22.5, 22.2,22.0, 19.3, 17.1, 16.3, 12.1, 10.3, 8.6.

Synthesis of Triazole 235

To a stirred solution of 330 (20 mg, 25 μmol) in THF (100 μL) was addedHunig's base (20 μL), azide 158 (16 mg, 50 μmol), and cuprous iodide(2.4 mg, 13 μmol). The resulting mixture was degassed by alternatelyapplying vacuum and purging with argon gas. The slurry was stirred underargon at ambient temperature for 4 h. The entire reaction mixture wasthen placed atop a silica gel flash chromatography column and elutedwith 50:1 CH₂Cl₂/2N NH₃ in MeOH to afford triazole 235 as a white solid(14 mg, 50% yield). Data for 235: MS (ESI) m/z 560.8 (M+2H)²⁺, 120.5(M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.60 (bs, 1H), 7.62 (s, 1H),7.40–7.20 (m, 1H), 7.00–6.78 (m, 2H), 6.55–6.20 (m, 2H), 5.10–4.90 (m,2H), 4.50 (d, J=10 Hz 1H), 3.18 (s, 3H), 2.28 (bs, 3H), 2.16 (bs, 3H),0.90 (m, 6H).

Synthesis of Triazole 236

To a stirred solution of 330 (20 mg, 25 μmol) in THF (100 μL) was addedHunig's base (20 μL), azide 189 (16 mg, 50 μmol), and cuprous iodide(2.4 mg, 13 μmol). The resulting mixture was degassed by alternatelyapplying vacuum and purging with argon gas. The slurry was stirred underargon at ambient temperature for 4 h. The entire reaction mixture wasthen placed atop a silica gel flash chromatography column and elutedwith 50:1 CH₂Cl₂/2N NH₃ in MeOH to afford the desired triazole adduct236 as a white solid (18 mg, 70% yield). Data for 236: MS (ESI) m/z518.2 (M+2H)²⁺, 1035.2 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.70(bs, 1H), 7.65 (s, 1H), 7.40–7.20 (m, 2H), 7.05 (dd, J=8, 2 Hz, 1H),6.78 (td, J=8, 2 Hz, 2H), 6.60–6.20 (m, 2H), 5.10–4.90 (m, 2H), 4.40 (d,J=7 Hz 1H), 3.86 (dd, J=9, 7 Hz, 1H), 3.21 (s, 3H), 2.22 (bs, 3H), 2.16(s, 3H), 0.82 (m, 6H).

Example 36 Synthesis of Triazoles 237–240

Scheme 59 illustrates the synthesis of triazoles 237–240. Propargylalcohol was alkylated to afford silylether 331 and the silylethersubsequently converted to tosylate 332. Alkylation of amine 171 with 332afforded alkyne 333. Cycloaddition of 333 with azides 189 and 158yielded triazoles 237 and 238 respectively. Hydrolysis of 237 and 238provided triazoles 239 and 240.

Synthesis of Silylether 331

To a stirred slurry of sodium hydride (0.28 g, 6.97 mmol) in DMF (30 mL)was added propargyl alcohol (0.41 mL, 6.97 mmol) dropwise over 5minutes. The mixture was stirred at room temperature for 45 min., then2-[t-butyldimethylsiloxy]-bromoethane (1.8 mL, 8.4 mmol) was added inone portion. After 16 hours the reaction mixture was poured into water(100 mL) and extracted with 1:1 hexane/ether (3×50 mL). The combinedorganic extracts were washed with brine, dried on MgSO₄, filtered andconcentrated in vacuo to afford 331 as a colorless oil which was usedas-is without further purification (1.38 g, 92% yield).

Synthesis of Tosylate 332

Silylether 331 (0.86 g, 4 mmol) was dissolved in acetonitrile (20 mL) ina plastic culture tube and cooled to 0° C. Aqueous HF (48% w/w, 1 mL)was then added and the solution stirred at 0° C. for 3 hours. Thereaction mixture was poured slowly into 100 mL saturated aqueous NaHCO₃and extracted with ether (3×50 mL). The combined organic extracts werewashed with brine, dried (K₂CO₃), filtered, and concentrated to afford acolorless oil (0.5 g). This oil was dissolved in anhydrous CH₂Cl₂ (5mL), cooled to 0° C., and then Hunig's base was added (2 mL) followed bytosyl chloride (0.76 g, 4.0 mmol). The reaction mixture was allowed towarm to room temperature and stirred for 6 hours. The solution wasdiluted with CH₂Cl₂ (50 mL) and washed with saturated aqueous NaHCO₃ andbrine. The aqueous washes were back-extracted with CH₂Cl₂ (50 mL). Thecombined organic extracts were dried on MgSO₄, filtered, andconcentrated to give 332 as a colorless oil (0.81 g, 80% yield). Datafor 332: ¹HNMR (300 MHz, CDCl₃): δ 7.74 (m, 2H), 7.27 (m, 2H), 4.12 (t,J=5 Hz, 2H), 4.05 (d, J=2 Hz, 2H), 3.66 (t, J=5 Hz, 2H), 2.38 (s, 3H),2.34 (t, J=2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃): δ 144.8, 133.0, 129.8,128.0, 78.9, 75.0, 68.8, 67.1, 58.4, 21.6.

Synthesis of Alkyne 333

A 20 mL vial was charged with tosylate 332 (0.20 g, 0.82 mmol),N-desmethyl azithromycin 171 (0.5 g, 0.68 mmol), and Hunig's base (10mL) and then purged with argon gas and sealed. The solution was stirredin a 100° C. oil bath for 6 h. After cooling to room temperature, thereaction mixture was poured into saturated aqueous NaHCO₃ (50 mL) andextracted with CH₂Cl₂ (3×50 mL). The combined organic extracts werewashed with brine, dried over K₂CO₃, filtered, and concentrated toafford 0.65 g of an off-white solid. Purification by silica gel flashchromatography (25 mm×6″ column eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOH)gave 333 as a white solid (0.22 g, 37% yield). Data for 333: MS (ESI)m/z 409.2 (M+2H)²⁺, 817.0 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ7.50 (bs, 1H), 4.87 (d, J=4 Hz, 1H), 4.55 (dd, J=10, 2 Hz, 1H), 4.35 (d,J=7 Hz, 1H), 4.20 (dd, J=7, 2 Hz, 1H), 4.06 (d, J=2 Hz, 2H), 4.05–3.90(m, 1H), 3.57 (d, J=7 Hz, 1H), 3.51 (t, J=6 Hz, 1H), 3.38 (d, J=6 Hz,1H), 3.24 (s, 3H), 3.15 (dd, J=10, 7 Hz, 1H), 2.93 (t, J=10 Hz, 1H),2.24 (s, 3H), 2.23 (s, 3H), 0.86 (m, 6H); ¹³C NMR (75 MHz,): δ 177.8,106.84, 95.05, 82.3, 79.3, 76.0, 74.3, 73.1, 70.6, 69.9, 69.5, 65.8,62.35, 60.34, 52.1, 44.6, 41.9, 37.3, 36.5, 36.1, 29.6, 26.7, 25.8,21.2, 20.8, 18.6, 16.1, 15.9, 14.2, 10.9, 7.8.

Synthesis of Triazole 237

To a stirred solution of 333 (50 mg, 61 μmol) in THF (150 μL) was addedHunig's base (30 μL), azide 189 (20 mg, 86 μmol), and cuprous iodide (6mg, 33 μmol). The resulting mixture was degassed by alternately applyingvacuum and purging with argon gas. The slurry was stirred under argon atambient temperature for 4 h. The entire reaction mixture was then placedatop a silica gel flash chromatography column and eluted with 50:1CH₂Cl₂/2N NH₃ in MeOH to afford the desired triazole adduct 237 as awhite solid (31 mg, 70% yield). Data for 237: MS (ESI) m/z 527.4(M+2H)²⁺, 1075.4 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.10 (bs,1H), 7.72 (s, 1H), 7.40–7.20 (m, 2H), 7.05 (dd, J=8, 2 Hz, 1H), 6.78(td, J=6, 2 Hz, 2H), 5.10–4.90 (m, 2H), 4.80–4.60 (m, 4H), 4.40 (d, J=7Hz, 1H), 4.22 (d, J=4 Hz, 1H), 4.09 (t, J=9 Hz, 1H), 4.10–3.95 (m, 1H),3.89 (dd, J=9, 6 Hz, 1H), 3.34 (s, 3H), 3.16 (dd, J=10, 8 Hz, 1H), 2.32(s, 3H), 2.30 (s, 3H), 0.90 (m, 6H).

Synthesis of Triazole 238

To a stirred solution of 333 (35 mg, 43 μmol) in THF (150 μL) was addedHunig's base (30 μL), azide 158 (28 mg, 86 μmol), and cuprous iodide (4mg, 21 μmol). The mixture was degassed by alternately applying vacuumand purging with argon gas. The mixture was stirred under argon atambient temperature for 4 h. The entire reaction mixture was then placedatop a silica gel flash chromatography column and eluted with 50:1CH₂Cl₂/2N NH₃ in MeOH to afford the desired triazole adduct as a whitesolid (24 mg, 50% yield). Data for 238: MS (ESI) m/z 569.9 (M+2H)²⁺,1160.4 (M+Na)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.05 (bs, 1H), 7.80(s, 1H), 7.33 (dd, J=14, 2 Hz, 1H), 7.05 (dd, J=9, 2 Hz, 1H), 6.88 (t,J=9 Hz, 1H), 5.18–5.00 (m, 2H), 4.80–4.60 (m, 4H), 4.50 (d, J=7 Hz 1H),4.13 (t, J=9 Hz, 1H), 3.92 (dd, J=9, 6 Hz, 1H), 3.34 (s, 3H), 2.32 (s,3H), 2.30 (s, 3H), 0.90 (m, 6H).

Synthesis of Triazole 239

Compound 237 (10 mg, 9.8 μmol) was dissolved in EtOH (0.8 mL) and 1N HCl(aq) was then added (0.2 mL) and the solution stirred at roomtemperature for 16 h. The reaction mixture was diluted with 10 mL aq.0.2N HCl and washed with CH₂Cl₂ (3×10 mL). The aqueous layer was thenadjusted to pH 10 by addition of 2N KOH and extracted with CH₂Cl₂ (2×10mL). The latter two extracts were dried on K₂CO₃, filtered andconcentrated to afford triazole 239 as a solid (7 mg, 80% yield). Datafor 239: MS (ESI))₇/z 448.3 (M+2H)²⁺, 895.3 (M+H)⁺.

Synthesis of Triazole 240

Compound 238 (10 mg, 8.7 μmol) was dissolved in EtOH (1.6 mL) and 1N HCl(aq) was then added (0.4 mL) and the solution stirred at roomtemperature for 12 h. The reaction mixture was diluted with 10 mL aq.0.2N HCl and washed with CH₂Cl₂ (3×10 mL). The aqueous layer was thenadjusted to pH 10 by addition of 2N KOH and extracted with CH₂Cl₂ (2×10mL). The latter two extracts were dried on K₂CO₃, filtered andconcentrated to afford triazole 240 as a solid (6 mg, 87% yield). Datafor 240: MS (ESI) m/z 434.4 (M+2H)²⁺, 867.2 (M+H)⁺, 889.3 (M+Na)⁺.

Example 37 Synthesis of Ketolides 237–240

Scheme 60 depicts the synthesis of triazoles 241 and 242. Alkyne 197 wasprotected as diacetate 334, and then 334 was treated with sodiumhexamethyldisilylazide and carbonyldiimidazole to provide imidazolecarbamate 335. Michael addition of ammonia to 335 was followed byclosure of the amine group onto the imidazole carbamate to affordcarbamate 336. Seleective hydrolysis of 336 afforded alcohol 337 whichwas subsequently oxidized with the Dess-Martin periodinane to yieldketolide 338. Deprotection of 338 gave alkyne 339, which was treatedwith azides 158 and 189 to provide triazoles 241 and 242 respectively.

Synthesis of Diacetate 334

Alkyne 197 (1.50 g, 1.90 mmol) was dissolved in 5 mL methylene chlorideand the mixture cooled to 0° C. Dimethylaminopyridine (47 mg, 0.38 mmol)and triethylamine (0.8 mL, 5.7 mmol) were added, followed by aceticanhydride (0.54 mL, 5.7 mmol). The mixture was allowed to warm to roomtemperature and stirred for 1.5 h. Methylene chloride (50 mL) was addedand the mixture washed with sat. aqueous NaHCO₃, and then brine. Theorganic phase was dried (K₂CO₃) and evaporated to afford 1.9 g of awhite solid. The crude solid was purified by silica gel flashchromatography (25 mm×6″ column eluted with 40:1 CH₂Cl₂/2N NH₃ in MeOH)to afford 334 as a white solid (1.4 g, 86% yield). Data for 334: MS(ESI) m/z 870.2 (M+H)⁺, 892.3 (M+Na)⁺.

Synthesis of Imidazole Carbamate 335

A solution of 334 (0.8 g, 0.92 mmol) in 5.0 mL THF was cooled to −40°C., NaHMDS (1.2 mL of a 1.0 M THF soln.) was added dropwise to thestirred solution over 5 min., and the mixture was stirred at −40° C. for40 min. A solution of carbonyldiimidazole (0.60 g, 3.7 mmol) in 8 mL ofa 5:3 mixture of THF and DMF was then added over a period of 30 minutesby syringe-pump. Ten minutes after the addition was complete the coldbath was removed and the reaction mixture was allowed to warm to roomtemperature. After 16 h the reaction mixture was diluted with EtOAc (20mL) and the washed with sat. aqueous NaHCO₃ and brine. The organic phasewas dried (Na₂SO₄), filtered, and evaporated to afford 335 as anoff-white solid which was used without further purification (0.92 g,100% yield). Data for 335: MS (ESI) m/z 968.4 (M+Na)⁺.

Synthesis of Carbamate 336

A solution of 335 (0.94 g, 0.92 mmol) in acetonitrile (10 mL) wastreated with 15% aqueous ammonia (2 mL) and the mixture stirred at roomtemperature for 40 hours. The reaction mixture was diluted with EtOAc(50 mL), and washed with sat. aqueous NaHCO₃ and brine, the aqueouswashes were back-extracted twice with 50 mL portions of EtOAc. Thecombined organic extracts were dried (Na₂SO₄) and evaporated to afford1.3 g of an off-white solid. Purification by silica gel flashchromatography (25 mm×6″ column eluted with 1:3 acetone/hexanes) gave260 mg of 336 (31% yield) along with 100 mg of its C-10 epimer and 450mg of a mixture of the two. Data for 336: MS (ESI) m/z 895.2 (M+H)⁺,917.3 (M+Na)⁺.

Synthesis of Alcohol 337

A solution of 336 (209 mg, 0.221 mmol) in 0.1 N aqueous HCl (5 mL) wasstirred at room temperature for 8 h. The reaction mixture wasneutralized with with saturated aqueous NaHCO₃ (50 mL) and extractedwith methylene chloride (3×25 mL). The combined organic extracts werewashed with brine, dried (K₂CO₃), filtered, and evaporated to give 190mg of a white solid. The crude product was chromatographed on silica gelusing a 3:1 hexane/acetone as the eluant to provide 337 (145 mg, 94%yield) as a white solid. Data for 337: MS (ESI) m/z 695.2 (M+H)⁺, 717.1(M+Na)⁺.

Synthesis of Ketolide 338

To a stirred solution of 337 (80 mg, 0.115 mmol) in methylene chlorideat 0° C. was added Dess-Martin periodinane (59 mg, 0.138 mmol). Thereaction mixture was stirred at ambient temperature for 12 hours thenplaced directly on a silica gel chromatography column and eluted with3:1 hexane/acetone to afford ketolide 338 (62 mg, 78% yield) as a whitesolid. Data for 338: MS (ESI) m/z 693.1 (M+H)⁺, 715.3 (M+Na)⁺.

Synthesis of Alkyne 339

A methanol solution of 338 (62 mg, 0.090 mmol) was stirred at 50° C. for16 h. The reaction mixture was concentrated in vacuo to give 339 as awhite solid (55 mg, 94% yield) which was used without furtherpurification. Data for 339: MS (ESI) m/z 651.2 (M+H)⁺, 673.1 (M+Na)⁺.

Synthesis of Triazole 241

To a stirred solution of 339 (20 mg, 31 μmol) in THF (310 μL) was addedHunig's base (26 μL), azide 158 (14.8 mg, 46 μmol), and cuprous iodide(5.8 mg, 31 μmol). The resulting mixture was stirred at ambienttemperature for 4 h. The entire reaction mixture was then placed atop asilica gel flash chromatography column and eluted with 50:1 CH₂Cl₂/2NNH₃ in MeOH to afford the desired triazole adduct 241 as a white solid(26 mg, 86% yield). Data for 241: MS (ESI) m/z 972.3 (M+H)⁺, 994.3(M+Na)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.60 (s, 1H), 7.41 (dd,J=14, 2 Hz, 1H), 7.00–6.60 (m, 2H), 6.75 (bs, 1H), 5.72 (dd, J=10, 3 Hz,1H), 5.01–4.90 (m, 1H), 4.75–4.52 (m, 3H), 4.33–4.05 (m, 3H), 2.18 (s,3H), 0.90 (t, J=7 Hz, 3H).

Synthesis of Triazole 242

To a stirred solution of 339 (18 mg, 28 μmol) in THF (310 μL) was addedHunig's base (24 μL), azide 189 (10 mg, 42 μmol) and cuprous iodide (5.3mg, 28 μmol). The resulting mixture was stirred at ambient temperaturefor 4 h. The entire reaction mixture was then placed atop a silica gelflash chromatography column and eluted with 50:1 CH₂Cl₂/2N NH₃ in MeOHto afford the desired triazole adduct 242 as a white solid (21 mg, 85%yield). Data for 242: MS (ESI) m/z 887.3 (M+H)⁺, 909.3 (M+Na)⁺; ¹HNMR(300 MHz, CDCl₃, partial): δ 7.65 (s, 1H), 7.55–7.30 (m, 2H), 7.10 (dd,J=8, 2 Hz, 1H), 6.82–6.70 (m, 1H), 6.75 (bs, 1H), 5.70 (dd, J=10, 3 Hz1H), 5.18–4.99 (m, 1H), 4.80–4.52 (m, 3H), 4.33–4.05 (m, 3H), 2.20 (bs,3H), 0.90 (t, J=7 Hz, 3H).

Example 38 Synthesis of Isoxazolines 243–245

Scheme 61 depicts the synthesis of isoxazolines 243–245. Knownhydroxyiminoyl chloride 340 (J. Med. Chem. 2003, 46, 284) was convertedto isoxazoline alcohol 341. The alcohol group of 341 was transformed tothe azide 342, an intermediate used in subsequent aromatic substitutionchemistry with nucleophiles to produce azides 343, 344 and 345. Azide345 was acylated to provide azide 346. The cycloaddition of azides 343,344, and 346 with alkyne 173 yielded target isoxazolines 243, 245, and244 respectively.

Synthesis of Alcohol 341

To a solution of allyl alcohol (15.6 mL, 0.23 mol) in 600 mL chloroformwas added a 1M solution of diethyl zinc in hexanes (276 mL, 0.276 mol)between −10° C. to 0° C. After stirring for 10 min, (+)-diisopropylL-tartrate (9.68 mL, 45.9 mmol) was added and the solution was stirredat 0° C. for 1 h. Dioxane (24 mL, 0.282 mol) was added followed byhydroxyiminoyl chloride 340 (40 g, 0.209 mol) and the solution wasstirred at −5° C. to 0° C. for 1½ h, then poured into 1M citric acid/ice(400 mL) and extracted with dichloromethane (2×200 mL). The combinedorganic extract was washed with water (100 mL), brine (100 mL), dried(Na₂SO₄) and evaporated to a volume of 50 mL. 1-Chlorobutane (250 mL)was added and again the solution evaporated to a volume of 50 mL. Thebeige suspension was filtered, washed with 1-chlorobutane (2×10 mL) anddried to afford 14.5 g of alcohol 341. The remaining supernatant wasevaporated and purified by flash-chromatography (eluant: hexanes-ethylacetate 2:1) yielding and additional 22.0 g of alcohol 341. The combinedportions of alcohol 341 were recrystallized from 120 mL1-chlorobutane-hexanes 4:1, yielding pure alcohol 341 (31.1 g, 70%yield, ee: 95% as determined by Mosher ester). Data for 341: ¹HNMR (300MHz, CDCl₃): δ 7.55–7.45 (m, 1H), 7.39–7.12 (m, 2H), 4.95–4.83 (m, 1H),3.91 (dd, J=1, 2 Hz, 1H), 3.69 ((dd, J=1, 2 Hz, 1H), 3.40–3.21 (m, 2H),2.20 (br s, 1H).

Synthesis of Azide 342

To a solution of 341 (3.0 g, 14.1 mmol) in 60 mL dichloromethane wasadded Et₃N (3.53 mL, 25.2 mmol) followed by MsCl (1.31 mL, 16.9 mmol) at0° C. The mixture was stirred at 0° C. for 30 min, then poured into 30mL water/ice and extracted with dichloromethane (2×50 mL). The combinedorganic extract was washed with water (2×30 mL), brine (30 mL), dried(Na₂SO₄) and evaporated. The residue was dissolved in 50 mL DMF, andNaN₃ (1.83 g., 28.1 mmol) was added and the mixture stirred at 80° C.for 2 h. The mixture was poured into 30 mL water/ice and extracted withethyl acetate (2×50 mL). The combined organic extract was washed withwater (2×30 mL), brine (30 mL), dried (Na₂SO₄) and evaporated. Theresidual oil was crystallized with 20 mL 1-chlorobutane-hexanes 2:1,yielding azide 342 (3.0 g, 89%). Data for 342: ¹HNMR (300 MHz, CDCl₃): δ7.50–7.41 (m, 1H), 7.35–7.05 (m, 2H), 4.92–4.81 (m, 1H), 3.51–3.05 (m,4H).

Synthesis of Azide 343

A mixture of 342 (400 mg, 1.68 mmol) and K₂CO₃ (302 mg, 2.18 mmol) in 6mL morpholine was stirred at 120° C. for 48 h, then poured into 20 mLwater/ice and extracted with ethyl acetate (2×10 mL). The combinedorganic extract was washed with water (2×10 mL), brine (10 mL), dried(Na₂SO₄) and evaporated. The residue was purified byflash-chromatography (eluant: hexanes-ethyl acetate 2:1) yielding azide343 (320 mg, 63%). Data for 343: MS (ESI) m/z 306 (M+H)⁺; ¹HNMR (300MHz, CDCl₃): δ 7.38–7.23 (m, 2H), 6.80–6.78 (m, 1H), 4.90–4.75 (m, 1H),3.83–3.75 (m, 4H), 3.48–3.25 (m, 4H), 3.18–3.02 (m, 4H).

Synthesis of Azide 344

To a solution of imidazole (214 mg, 3.15 mmol) in 5 mL DMF was added NaH(60% dispersion in paraffin oil, 100 mg, 2.52 mmol) at 0° C. Afterstirring the mixture for 30 min, the azide 342 (0.5 g, 2.1 mmol) wasadded. The mixture was stirred at room temperature overnight and then60° C. for 2 h, and then poured into 40 mL water/ice and extracted withethyl acetate (3×20 mL). The combined organic extract was washed withwater (3×20 mL), brine (10 mL), dried (Na₂SO₄) and evaporated. Theresidue was purified by flash-chromatography (eluant: ethyl acetatefollowed by ethyl acetate-MeOH 20:1) yielding azide 344 (390 mg, 65%).Data for 344: ¹HNMR (300 MHz, CDCl₃): δ 7.92 (s, 1H), 7.72–7.45 (m, 3H),7.39–7.23 (m, 2H), 5.10–4.96 (m, 1H), 3.69–3.41 (m, 3H), 3.31–3.20 (m,1H).

Synthesis of Azide 345

A mixture of azide 342 (1.0 g, 4.2 mmol), K₂CO₃ (755 mg, 5.5 mmol) andpiperazine (15 g, 175 mmol) was dissolved in 9 mL DMF. The mixture wasstirred at 120° C. for 3 h, then poured into 50 mL water/ice andextracted with ethyl acetate-isopropanol 95:5 (3×30 mL). The combinedorganic extract was washed with water (3×20 mL), brine (10 mL), dried(Na₂SO₄) and evaporated. The residue was purified byflash-chromatography (eluant: ethyl acetate-MeOH 3:1) yielding azide 345(793 mg, 63%). Data for 345: ¹HNMR (300 MHz, CDCl₃): δ 7.52–7.39 (m,2H), 7.08–6.95 (m, 1H), 5.05–4.92 (m, 1H), 3.63–3.41 (m, 3H), 3.33–3.10(m, 9H), 1.85 (br s, 1H).

Synthesis of Azide 346

To a solution of azide 345 (300 mg, 0.99 mmol) in 6 mldichloromethane-DMF 2:1 was added glycolic acid (97.8 mg, 1.29 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (284mg, 1.48 mmol) and diisopropyl ethylamine (0.344 mL, 1.98 mmol) at 0° C.The solution was stirred at room temperature over the weekend and thenpoured into 20 mL 5% aqueous Na₂CO₃/ice and extracted with ethyl acetate(2×15 mL). The combined organic extract was washed with water (2×10 mL),10 mL 1M aqueous HCl, water (2×10 mL), brine (10 mL), dried (Na₂SO₄) andevaporated. The residue was purified by flash-chromatography(eluant:ethyl acetate) yielding azide 346 (51 mg, 15%). Data for 346:¹HNMR (300 MHz, CDCl₃): δ 7.39–7.25 (m, 2H), 6.91–6.80 (m, 1H),4.91–4.79 (m, 1H), 4.15 (s, 2H), 3.83–3.75 (m, 2H), 3.50–3.26 (m, 5H),3.18–3.04 (m, 5H).

Synthesis of Isoxazoline 243

To a solution of alkyne 173 (100 mg, 0.127 mmol) in 4 mL acetonitrilewas added azide 343 (39 mg, 0.127 mmol), 2,6-lutidine (0.0163 mL, 0.139mmol) and CuI (24 mg, 0.127 mmol). The mixture was stirred overnight atroom temperature, then poured into 10 mL 5% aqueous NH₃/ice andextracted with ethyl acetate (3×20 mL). The combined organic extract waswashed with water (2×10 mL), brine (10 mL), dried (Na₂SO₄) andevaporated. The residue was purified by flash-chromatography (eluant:ethyl acetate-MeOH 5:1) yielding 243 (71 mg, 51%). Data for 243: MS(ESI) m/z 1092 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.31–8.21 (brs, 1H), 7.51 (s, 1H), 7.31–7.12 (m, 2H), 6.81 (t, J=1 Hz, 1H), 5.05–4.90(s, 1H), 4.65–3.90 (m, 5H), 3.81–3.74 (m, 2H).

Synthesis of Isoxazoline 244

To a solution of alkyne 173 (100 mg, 0.127 mmol) in 4 mL acetonitrilewas added azide 346 (46 mg, 0.127 mmol), 2,6-lutidine (0.0163 mL, 0.139mmol) and CuI (14.5 mg, 0.076 mmol). The mixture was stirred overnightat room temperature, then poured into 10 mL 5% aqueous NH₃/ice andextracted with ethyl acetate (3×20 mL). The combined organic extract waswashed with water (2×10 mL), brine (10 mL), dried (Na₂SO₄) andevaporated. The residue was purified by flash-chromatography (eluant:ethyl acetate-MeOH 5:1) yielding 244 (58 mg, 40%). Data for 244: MS(ESI) m/z 1049 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃ partial): δ 7.54 (s, 1H),7.31–7.13 (m, 2H), 7.85–7.72 (m, 1H), 5.10–4.95 (m, 1H).

Synthesis of Isoxazoline 245

To a solution of alkyne 173 (100 mg, 0.127 mmol) in 4 mL acetonitrilewas added 344 (36.3 mg, 0.127 mmol), 2,6-lutidine (0.0163 mL, 0.139mmol) and CuI (24 mg, 0.127 mmol). The mixture was stirred overnight atroom temperature, then poured into 10 mL 5% aqueous NH₃/ice andextracted with ethyl acetate (3×20 mL). The combined organic extract waswashed with water (2×10 mL), brine (10 mL), dried (Na₂SO₄) andevaporated. The residue was purified by flash-chromatography (eluant:ethyl acetate-MeOH 5:1) yielding 245 (60 mg, 44%). Data for 245: MS(ESI) m/z 1073 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 7.8 (s, 1H),7.50–7.30 (m, 3H), 7.21–7.14 (m, 3H), 5.19–4.95 (m, 2H), 4.68–3.90 (m,7H).

Example 39 Synthesis of Isoxazolines 246–250

Scheme 62 depicts the synthesis of isoxazolines 246–250. Hydroxyiminoylchloride 347 was converted to isoxazoline alcohol 348 as described inthe literature (J. Med. Chem. 2003, 46, 284). The alcohol group of 348was transformed to the azide 349, which was treated with alkyne 173 toafford isoxazoline 246. Azide 349 was coupled to substituted boronicacids to afford azides 354 and 355, which were treated with alkyne 173to afford isoxazolines 248 and 249. Alcohol 348 was coupled tosubstituted boronic acids to provide alcohols 350 and 351, which weresubsequently converted to azides 352 and 353. The cycloaddition of 352and 353 with alkyne 173 gave isoxazolines 250 and 247 respectively.

Synthesis of Azide 349

To a solution of alcohol 348 (2.00 g, 7.81 mmol) in CH₂CH₂ (40 mL) at 0°C. was added Et₃N (2.20 mL, 15.6 mmol), followed by the dropwiseaddition of MsCl (911 μL, 11.7 mmol). The mixture was stirred at 0° C.for 30 min, then poured into 30 mL water/ice and extracted with Et₂O (50mL×3). The combined organic extract was washed with water (50 mL×3),dried over MgSO₄, and evaporated to give 2.70 g of the intermediatemesylate of suitable purity to be used in the next step. The mesylate(2.70 g) was dissolved in DMF (30 mL), NaN₃ (2.10 g, 31.238 mmol) wasadded, and the mixture stirred at 80° C. for 2.5 h. The mixture waspoured into water/ice (150 mL) and Et₂O (300 mL). The organic extractwas washed with water (150 mL×3), dried over MgSO₄, and concentrated toafford azide 349 as a white crystalline solid (2.10 g, 96% yield). Datafor 349: ¹HNMR (300 MHz, CDCl₃): δ 7.54 (s, 4H), 4.93 (dddd, J=10, 8, 5,5 Hz, 1H), 3.56 (dd, J=13, 5 Hz, 1H), 3.45 (dd, J=13, 5 Hz, 1H), 3.42(dd, J=17, 11 Hz, 1H), 3.21 (dd, J=17, 7 Hz, 1H).

Synthesis of Alcohol 350

A mixture of alcohol 348 (1.00 g, 3.91 mmol), 4-methylthiophenyl boronicacid (1.10 g, 5.86 mmol), palladium acetate (18 mg, 0.078 mmol),2-(di-tert-butylphosphino)biphenyl (47 mg, 0.156 mmol) and KF (678 mg,11.7 mmol) in THF (10 mL) at room temperature was degassed by bubblingargon through the mixture. The mixture was then stirred at roomtemperature for 15 h. The red suspension was poured into 10 mL sat.Na₂CO₃ and 100 ml water. The mixture was extracted with 15% isopropylalcohol in CH₂CH₂ (200 mL×3). The combined organic layer was washed withwater (100 mL×3), dried over MgSO₄, and evaporated to provide 350 (1.2g, 100% yield). Data for 350: ¹HNMR (300 MHz, CDCl₃): δ 7.73 (d, J=8 Hz,2H), 7.62 (d, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 2H), 7.33 (d, J=8 Hz, 2H),4.90 (dddd, J=13, 8, 5, 3 Hz, 1H), 3.90 (ddd, J=12, 6, 3 Hz, 1H), 3.71(ddd, J=12, 8, 5 Hz, 1H), 3.43 (dd, J=17, 11 Hz, 1H), 3.32 (dd, J=17, 8Hz, 2H), 2.53 (s, 3H), 1.90 (dd, J=8, 6 Hz, 1H).

Synthesis of Alcohol 351

Alcohol 351 was synthesized by the same procedure as reported foralcohol 350 using 3-cyanophenyl boronic acid (956 mg, 5.86 mmol). Themixture was extracted with CH₂CH₂ (100 mL×3). The residue was isolatedby flash-chromatography on silica gel (2/100 MeOH/CH₂CH₂ as eluant), toafford alcohol 351 (1.0 g, 92% yield). Data for 351: ¹HNMR (300 MHz,CDCl₃): δ 7.90–7.77 (m, 4H), 7.69–7.54 (m, 4H), 4.92 (dddd, J=11, 8, 5,3 Hz, 1H), 3.92 (ddd, J=12, 6, 3 Hz, 1H), 3.72 (ddd, J=12, 8, 5 Hz, 1H),3.45 (dd, J=17, 11 Hz, 1H), 3.34 (dd, J=17, 8 Hz, 1H), 1.92 (dd, J=8, 6Hz, 1H).

Synthesis of Azide 352

To a suspension of alcohol 350 (2.00 g, 6.68 mmol) in CH₂CH₂ (40 mL) at0° C. was added Et₃N (1.90 mL, 13.4 mmol), and then MsCl (776 μL, 10.0mmol) dropwise. The mixture was stirred at room temperature for 2 h andthen refluxed for 3 h. The mixture was cooled to room temperature andEtOAc/Hexane (150 mL/50 mL) was added. The white solid was collected,washed with water (30 mL×3), and dried under vacuum to afford 2 g ofcrude mesylate. The crude mesylate obtained above (0.50 g, 1.33 mmol)was suspended in DMF (8 mL), NaN₃ (348 mg, 5.30 mmol) was added and themixture stirred at 80° C. for 4 h. The mixture was poured into water/ice(50 mL), extracted by EtOAc (30 mL×4), dried over MgSO₄, the residue wasisolated by chromatography on silica gel (40/60 EtOAc/hexane as eluant)to afford azide 352 (305 mg, 71% yield) as a white powder. Data for 352:¹HNMR (300 MHz, CDCl₃): δ 7.73 (d, J=8 Hz, 2H), 7.62 (d, J=8 Hz, 2H),7.55 (d, J=8 Hz, 2H), 7.33 (d, J=8 Hz, 2H), 4.94 (m, 1H), 3.55 (dd,J=13, 5 Hz, 1H), 3.48 (m, 2H), 3.25 (dd, J=17, 7 Hz, 1H), 2.97 (s, 3H).

Synthesis of Azide 353

To a solution of alcohol 351 (1.00 g, 3.59 mmol) in CH₂CH₂ (20 mL) at 0°C. was added Et₃N (1.00 mL, 7.19 mmol), followed by the dropwiseaddition of MsCl (419 μL, 5.39 mmol). The mixture was stirred at 0° C.for 30 min, and then at room temperature for 2 h. The mixture was pouredinto 100 mL water/ice and EtOAc/hexane 150 mL/50 mL). The combinedorganic extract was washed with water (100 mL×3), dried over MgSO₄, andevaporated to give 1.20 g of the crude mesylate which was used directlyin the mext step without further purification. The mesylate (1.20 g) wasdissolved in DMF (20 mL), and NaN₃ (884 mg, 13.47 mmol) was added, andthe mixture was stirred at 80° C. for 2.5 h. The mixture was poured intowater/ice (150 mL) and EtOAc (250 mL). The organic extract was washedwith water (100 mL×3), dried over MgSO₄, and evaporated. The residue wasseparated by chromatography on silica gel (30/70 EtOAc/hexane as eluant)to afford azide 353 (836 mg, 77% yield) as a white crystalline solid.Data for 353: ¹HNMR (300 MHz, CDCl₃): δ 7.90–7.77 (m, 4H), 7.69–7.50 (m,4H), 4.97 (dddd, J=15, 7, 5, 5 Hz, 1H), 3.57 (dd, J=13, 5 Hz, 1H), 3.50(m, 2H), 3.26 (dd, J=17, 7 Hz, 1H).

Synthesis of Azide 354

A mixture of azide 349 (300 mg, 1.07 mmol), 4-(hydroxymethyl)phenylboronic acid (286 mg, 1.60 mmol), palladium acetate (5 mg, 0.021 mmol),2-(di-tert-butylphosphino)biphenyl (13 mg, 0.043 mmol) and KF (188 mg,3.20 mmol) in THF (4 mL) at was degassed by bubbling argon through themixture. The mixture was then stirred at room temperature for 15 h. Thered suspension was poured into 5 mL sat. Na₂CO₃ and 20 mL water. Themixture was extracted with 5% MeOH/CH₂CH₂ (200 mL). The combined organiclayer was washed by water (100 mL×3), dried over MgSO₄, and evaporated.The residue was purified by chromatography on silica gel (1.5/100MeOH/CH₂CH₂ as eluant) to afford azide 354 (220 mg, 67% yield). Data for354: ¹HNMR (300 MHz, CDCl₃): δ 7.75 (d, J=8 Hz, 2H), 7.65 (d, J=8 Hz,2H), 7.62 (d, J=8 Hz, 2H), 7.47 (d, J=8 Hz, 2H), 4.95 (dddd, J=10, 8, 5,5 Hz, 1H), 4.76 (d, J=6 Hz, 2H), 3.55 (dd, J=13, 5 Hz, 1H), 3.50 (dd,J=17, 11 Hz, 2H), 3.25 (dd, J=17, 7 Hz, 1H), 1.71 (dd, J=5, 5 Hz, 1H).

Synthesis of Azide 355

A mixture of azide 349 (300 mg, 1.07 mmol), 4-cyanophenyl boronic acid(261 mg, 1.60 mmol), palladium acetate (5 mg, 0.021 mmol),2-(di-tert-butylphosphino)biphenyl (13 mg, 0.043 mmol) and KF (188 mg,3.20 mmol) in THF (4 mL) at room temperature was degassed by bubblingargon through the mixture. The mixture was then stirred at roomtemperature for 15 h. The red suspension was poured into 5 mL sat.Na₂CO₃ and 20 mL water. The mixture was extracted with CH₂CH₂ (50 mL×3).The combined organic layer was washed by water (100 mL×3), dried overMgSO₄, and evaporated. The residue was purified by chromatography onsilica gel (30/70 EtOAc/hexane as eluant) to afford azide 355 (300 mg,93% yield). Data for 355: ¹HNMR (300 MHz, CDCl₃): δ 7.83–7.63 (m, 8H),4.97 (dddd, J=16, 7, 5, 5 Hz, 1H), 3.58 (dd, J=13, 5 Hz, 1H), 3.50 (dd,J=16, 10 Hz, 1H), 3.40 (dd, J=13, 5 Hz, 1H), 3.27 (dd, J=16, 7 Hz, 1H).

General Procedure for the Synthesis of Isoxazolines 246–250

To a mixture of alkyne 173 (100 mg, 0.127 mmol), the appropriate azide(0.140 mmol, 1.1 eq) in acetonitrile (4.0 mL) at room temperature underargon was added 2,6-lutidine (22 μL, 0.191 mmol, 1.1 eq), followed bythe addition of copper (I) iodide (12 mg, 0.064 mmol). The mixture wasstirred at room temperature for 1.5 to 6 h. After the reaction wascomplete, 1 mL 5% NH₄OH was added. The mixture was stirred at roomtemperature for 10 min. The acetonitrile was removed under vacuum. Theaqueous phase was extracted with CH₂Cl₂ (30 mL×3), dried over Na₂SO₄,and evaporated. The residue was purified by chromatography on silica gel(20/80 to 30/70 MeOH/EtOAc) to provide isoxazolines 246 (116 mg, 85%yield), 247 (120 mg, 87% yield), 248 (120 mg, 87% yield), 249 (72 mg,52% yield), and 250 (93 mg, 66% yield).

Data for 246: MS (ESI) m/z 1067.6 (M−H)⁺; ¹HNMR (300 MHz, CDCl₃,partial): δ 7.56 (s, 1H), 7.53 (d, J=9 Hz, 2H), 7.74 (d, J=9 Hz, 2H),5.12 (br s, 1H), 4.71–4.52 (m, 4H), 4.43 (d, J=7 Hz, 1H), 4.29 (br s,1H), 4.08 (m, 1H), 3.69–3.16 (m, 10H), 3.03 (dd, J=10, 10 Hz, 1H).

Data for 247: MS (ESI) m/z 1090.5 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 7.88 (s, 1H), 7.83 (d, J=8 Hz, 1H), 7.75–7.55 (m, 7H), 5.17 (br s,1H), 5.09 (br s, 1H), 4.80–4.60 (m, 4H), 4.41 (d, J=7 Hz, 1H), 4.26 (brs, 1H), 4.09 (m, 1H), 3.68–3.18 (m, 10H).

Data for 248: MS (ESI) m/z 1090.3 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 7.77–7.60 (m, 9H), 5.17 (br s, 1H), 5.09 (br s, 1H), 4.71–4.55 (m,4H), 4.41 (d, J=7 Hz, 1H), 4.26 (br s, 1H), 4.09 (m, 1H), 3.67–3.20 (m,4H).

Data for 249: MS (ESI) nm/z 1095.4 (M)⁺; ¹HNMR (300 MHz, CDCl₃,partial): δ 7.69–7.57 (m, 7H), 7.46 (d, J=8 Hz, 2H), 5.12 (d, J=4 Hz,2H), 4.70–4.54 (m, 4H), 4.42 (d, J=7 Hz, 1H), 4.28 (br s, 1H), 4.08 (m,1H), 3.69–3.20 (m, 10H).

Data for 250: MS (ESI) m/z 1111.4 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 7.68–7.50 (m, 7H), 7.35 (d, J=8 Hz, 2H), 5.12 (br s, 1H), 4.71–4.54(m, 4H), 4.43 (d, J=8 Hz, 1H), 4.29 (br s, 1H), 4.07 (m, 1H), 3.69–3.20(m, 10H), 3.03 (dd, J=10, 10 Hz, 1H).

Example 40 Synthesis of Isoxazolines 251 and 252

Scheme 63 depicts the synthesis of isoxazoline 251. Hydroxyiminoylchloride 357 was made from the oxime (356) of 3,5-dichlorobenzaldehyde.The cycloaddition of 357 and allyl alcohol (via the intermediate nitrileoxide) afforded racemic isoxazoline alcohol 358. The alcohol wasconverted to azide 360 via the mesylate 359. The cycloaddition of 360with alkyne 173 yielded isoxazoline 251 (as a diasteromeric mixture).Isoxazoline 252 was synthesized (also as a diastereomeric mixture) bycarrying 3,5-difluorobenzaldehyde through the sequence of Scheme 63.

Synthesis of Oxime 356

A solution of 3,5-dichlorobenzaldehyde (2.0 g, 11.42 mmol) andhydroxylamine hydrochloride (0.87 g, 12.57 mmol) in ethanol (40 mL) andwater (80 mL) was cooled to 4° C., and NaOH (50%(w/w), 2.3 mL) wasadded. The reaction mixture was stirred for 3 h at room temperature. Thereaction mixture was then neutralized to pH 6.0, and partitioned withmethylene chloride and water. The aqueous layer was extracted twice withmethylene chloride, and the combined organic layer was washed withbrine, dried (Na₂SO₄), and evaporated to yield 356 (2.15 g, 99% yield)as a white solid. Data for 356: ¹HNMR (300 MHz, CDCl₃): δ 8.11 (s, 1H),7.45 (s, 1H), 7.34 (s, 1H).

Synthesis of Hydroximinoyl Chloride 357

To a solution of oxime 356 (2.15 g, 11.31 mmol) in dimethylformamide (10mL) was added N-chlorosuccinimide (1.5 g, 11.31 mmol). The reactionmixture was warmed to 50° C. for 1 h. The reaction was then diluted withethyl acetate (50 mL), and washed with brine, dried (Na₂SO₄), andevaporated to yield 357 (2.60 g, 100% yield). Data for 357: ¹HNMR (300MHz, CDCl₃): δ 7.8 (s, 1H), 7.50 (s, 1H), 7.17 (s, 1H).

Synthesis of Isoxazoline Alcohol 358

To a solution of hydroximinoyl chloride 357 (1.50 g, 6.68 mmol) inmethylene chloride (50 mL) was added allyl alcohol (0.45 mL, 6.68 mmol).The mixture was cooled to 0° C., and triethylamine (1.0 mL, 6.68 mmol)was added. The reaction mixture was slowly warmed to room temperature,stirred for 16 h, quenched with water (50 mL), and extracted twice withmethylene chloride. The combined organic layer was washed with brine,dried over Na₂SO₄, and evaporated to yield 358 (1.60 g, 100% yield).Data for 358: ¹HNMR (300 MHz, CDCl₃): δ 7.47 (s, 2H), 7.32 (s, 1H), 4.84(m, 1H), 3.82 (dd, J=15, 3 Hz, 1H), 3.62 (dd, J=16, 4 Hz, 1H), 3.23 (m,2H).

Synthesis of Mesylate 359

Alcohol 358 (1.60 g, 6.50 mmol) was dissolved in 5 mL methylenechloride, and the mixture cooled to 0° C. Triethylamine (1.8 mL, 13.0mmol) was added, followed by methanesulfonyl chloride (0.7 mL, 9.10mmol). The mixture was allowed to warm to room temperature and stirredfor 1 h. Methylene chloride (20 mL) was added, and the mixture washedtwice with 1N HCl, then twice with 10% aqueous sodium carbonate, andthen brine. The organic phase was dried (Na₂SO₄), and evaporated toyield mesylate 359 (1.60 g, 99% yield). Data for 359: ¹HNMR (300 MHz,CDCl₃): δ 7.67 (s, 2H), 7.56 (s, 1H), 5.22 (m, 1H), 4.51 (m, 2H), 3.60(m, 1H), 3.40 (dd, J=7, 15 Hz, 1H), 3.25 (s, 3H).

Synthesis of Azide 360

A solution of mesylate 359 (1.60 g, 6.15 mmol) in dimethylformamide (10mL) was treated with sodium azide (1.6 g, 24.60 mmol) and the mixtureheated to 80° C. for 3 h. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate (50 mL), and washed with brine(2×50 mL). Drying (Na₂SO₄), and evaporation provided azide 360 (1.28,77% yield) as a yellow oil of suitable purity for use in subsequentreactions. Data for 360: ¹HNMR (300 MHz, CDCl₃): δ 7.45 (s, 2H), 7.39(s, 1H), 3.51 (dd, J=17, 4 Hz, 1H), 3.35–3.20 (m, 2H), 3.13 (m, 1H).

Synthesis of Isoxazoline 251

A solution of alkyne 173 (170 mg, 0.220 mmol) in tetrahydrofuran (10 mL)was treated with azide 360 (0.08 g, 0.324 mmol),N,N-diisopropylethylamine (0.05 mL, 0.22 mmol) and copper (I) iodide(0.03 g, 0.160 mmol), and the mixture was stirred under argon at roomtemperature for 16 h. The reaction mixture was diluted with ethylacetate (50 mL), and washed with brine (2×50 mL). The organic phase wasdried and evaporated. The residue was purified by preparative thin layerchromatography (using 80% CH₂Cl₂, 20% MeOH, 1% NH₄OH as eluant) toprovide isoxazoline 251 (197 mg, 86% yield) as a yellow solid. Data for251: ¹HNMR (300 MHz, CDCl₃, partial): δ 7.36 (s, 2H), 7.22 (s, 1H), 4.96(m, 2H), 4.24 (m, 2H), 4.10 (m, 1H), 3.52–3.15 (m, 2H), 3.06 (s, 1H),2.59 (m, 2H).

Synthesis of Isoxazoline 252

This compound was made from alkyne 173 and the requisite 3,5-difluoroazide using the same procedures reported above for the synthesis ofisoxazoline 251. Data for 252: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.50(s, 1H), 7.10 (d, J=3 Hz, 2H), 6.86 (m, 1H), 5.10 (m, 1H), 5.08 (m, 1H),4.66 (m, 1H), 4.61 (m, 2H), 4.41 (m, 1H), 4.20 (m, 1H), 4.10 (m, 1H),3.68 (m, 2H), 3.32–3.22 (m, 2H), 2.84 (t, 2H).

Example 41 Synthesis of Triazoles 361–367

Scheme 64 depicts the synthesis of triazoles 361 and 362. Azide 416 wastreated with alkynes 173 and 174 to produce triazoles 361 and 362respectively.

Synthesis of Azide 416

Azide 416 was synthesized from 2-amino-3-methyl-thiazole using thechemistry reported in the literature (Brickner, S. J. et al. J. Med.Chem. 1996, 39, 673). Data for 416: ¹HNMR (300 MHz, CDCl₃): δ 6.59 (s,1H), 4.92–4.87 (m, 1H), 4.34 (t, J=9 Hz, 1H), 4.12 (dd, J=6, 3 Hz, 1H),3.73 (dd, J=3, 12 Hz, 1H), 3.61 (dd, J=3, 12 Hz, 1H), 2.35 (s, 3H).

Synthesis of Triazole 361

To a mixture of alkyne 173 (150 mg, 0.191 mmol), azide 416 (55 mg, 0.229mmol) and copper (I) iodide (18.3 mg, 0.096 mmol) was added THF (10 mL)and the mixture was repeatedly degassed and flushed with argon. Theni-Pr₂NEt (0.05 mL) was introduced and the mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into NH₄Cl (30 mL)and stirred for few minutes. Then NH₄OH (3 mL) was added and the mixturewas extracted with methylene chloride (3×40 ml). The combined organiclayer was dried (Na₂SO₄), concentrated and flash chromatographed oversilica gel (methylene chloride: MeOH:NH₄OH=12:1:0.025) to provide 150 mgof the product. Data for 361: MS (ESI) m/z 514 (M+2H)²⁺; ¹HNMR (300 MHz,CDCl₃, partial): δ 7.59 (s, 1H), 6.56 (s, 1H), 5.22–5.10 (m, 2H),4.79–4.62 (m, 4H), 4.46–4.39 (m, 2H), 4.28 (br d, J=3 Hz, 1H), 0.91–0.87(m, 6H).

Synthesis of Triazole 362

The cycloaddition of alkyne 174 (150 mg, 0.187 mmol) and azide 416 (49.2mg, 0.206 mmol) was performed under similar conditions as describedabove for the synthesis of 361 to afford 169 mg of 362. Data for 362: MS(ESI) m/z 521 (M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.49 (s,1H), 6.56 (s, 1H), 5.18–5.12 (m, 2H), 3.34 (s, 3H), 3.03 (t, J=9 Hz,1H), 0.91–0.87 (m, 6H).

Synthesis of Triazole 363

Triazole 363 (117 mg) was synthesized from alkyne 174 (100 mg, 0.125mmol) and azide 189 (29.7 mg, 0.126 mmol) following the same procedureas described above for compound 361. Data for 363: MS (ESI) m/z 519(M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.52 (s, 1H), 7.35–7.28(m, 2H), 7.08 (br d, J=8 Hz, 1H), 6.84 (dd, J=2, 8 Hz, 1H), 5.10–5.01(m, 2H), 4.29 (d, J=3 Hz, 1H), 3.23 (t, J=8 Hz, 1H), 3.03 (t, J=9 Hz,2H), 0.91–0.87 (m, 6H).

Synthesis of Triazole 364

Triazole 364 (141 mg) was synthesized from alkyne 174 (150 mg, 0.187mmol) and azide 277 (57.5 mg, 0.206 mmol) following the same procedureas described above for compound 361. Data for 364: MS (ESI) m/z 541(M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.52 (s, 1H), 7.22 (d, J=2Hz, 1H), 6.93 (dd, J=2, 8 Hz, 1H), 6.83 (t, J=9 Hz, 1H), 5.09 (d, J=5Hz, 1H), 5.05–4.98 (m, 1H), 4.45 (d, J=7 Hz, 1H), 3.88 (dd, J=6, 3 Hz,1H), 3.34 (s, 3H), 3.03 (t, J=9 Hz, 1H), 0.91–0.87 (m, 6H).

Synthesis of Triazole 365

Triazole 365 (200 mg) was synthesized from alkyne 174 (150 mg, 0.187mmol) and azide 266 (63.6 mg, 0.206 mmol) following the same procedureas described above for compound 361. Data for 365: MS (ESI) m/z 556(M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.52 (s, 1H), 7.28–7.23(m, 1H), 6.98–6.91 (m, 2H), 5.12 (d, J=5 Hz, 1H), 5.04–5.02 (m, 1H),4.45 (d, J=7 Hz, 1H), 4.28 (br d, J=3 Hz, 1H), 4.13–4.05 (m, 2H), 3.88(dd, J=6, 3 Hz, 1H), 3.74 (t, J=5 Hz, 2H), 3.34 (s, 3H), 3.03 (t, J=9Hz, 1H), 0.91–0.87 (m, 6H).

Synthesis of Triazole 366

The required 3,5-difluorophenyl oxazolidinone azide was synthesized from3,5-difluoroaniline using the same procedure as that used for thesynthesis of azide 189. Triazole 366 (157 mg) was synthesized fromalkyne 174 (150 mg, 0.187 mmol) and the 3,5-difluorophenyl oxazolidinoneazide (52.3 mg, 0.206 mmol) following the same procedure as describedabove for compound 361. Data for 366: MS (ESI) m/z 528.6 (M+2H)²⁺,1055.8 (M+H)⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ7.50 (s, 1H), 7.02(dd, J=2, 9 Hz, 2H), 6.62–6.55 (m, 1H), 5.14 (d, J=5 Hz, 1H), 5.10–5.02(m, 1H), 4.81 (d, J=6 Hz, 1H), 4.72 (d, J=4 Hz, 2H), 4.45 (d, J=7 Hz,1H), 3.93 (dd, J=6, 3 Hz, 1H), 3.34 (s, 3H), 3.23 (dd, J=7, 3 Hz, 1H),3.03 (t, J=10 Hz, 1H), 0.91–0.86 (m, 6H).

Synthesis of Triazole 367

Triazole 367 (200 mg) was synthesized from alkyne 174 (150 mg, 0.187mmol) and azide 323 (59.1 mg, 0.206 mmol) following the same procedureas described above for compound 361. Data for 367: MS (ESI) m/z 545(M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.58 (d, J=3 Hz, 1H), 7.50(s, 1H), 7.40 (d, J=9 Hz, 1H), 7.28–7.24 (m, 1H), 5.14 (d, J=4 Hz, 1H),5.10–5.02 (m, 1H), 4.44 (d, J=7 Hz, 1H), 4.29 (br d, J=2 Hz, 1H), 3.95(dd, J=6, 3 Hz, 1H), 3.34 (s, 3H), 3.23 (dd, J=7, 3 Hz, 1H), 3.03 (t,J=9 Hz, 1H), 0.91–0.86 (m, 6H).

Example 42 Synthesis of Triazoles 368–370

Scheme 65 depicts the synthesis of triazoles 368–370. The requiredazides 420, 424, and 428 were synthesized using standard methods fromthe appropriate anilines. The cycloaddition of these azides with alkyne173 afforded triazoles 368–370.

Synthesis of Azides 420, 424, 428

The azides were synthesized from the substituted anilines using thechemistry reported in the literature (Brickner, S. J. et al. J. Med.Chem. 1996, 39, 673).

Data for 420: MS (ESI) m/z 291.9 (M+H+CH₃CN)⁺, ¹H-NMR, (300 MHz, CDCl₃):δ 7.31 (t, J=8 Hz, 1H), 6.96–6.91 (m, 2H), 4.76 (m, 1H), 4.01 (t, J=9Hz, 1H), 3.73 (m, 1H), 3.63 (dd, J=13, 4 Hz, 1H), 3.50 (dd, J=14, 5 Hz,1H), 2.31 (s, 3H).

Data for 424: ¹H-NMR, (300 MHz, CDCl₃): δ 7.28 (dd, J=12, 2 Hz, 1H),7.08–7.00 (m, 2H), 4.71 (m, 1H), 3.98 (t, J=9 Hz, 1H), 3.74 (m, 1H),3.63 (dd, J=13, 4 Hz, 1H), 3.50 (dd, J=14, 5 Hz, 1H), 2.16 (d, J=2 Hz,3H).

Data for 428: ¹H-NMR, (300 MHz, CDCl₃) δ 7.29 (m, 1H), 7.19 (m, 1H),6.92 (t, J=9 Hz, 1H), 4.69 (m, 1H), 3.98 (t, J=9 Hz, 1H), 3.75 (m, 1H),3.62 (dd, J=13, 4 Hz, 1H), 3.50 (dd, J=13, 5 Hz, 1H), 2.21 (s, 3H).

Synthesis of Triazole 368

This compound was obtained from the reaction of alkyne 173 (0.115 g,0.148 mmol) with azide 420 (0.048 g, 0.192 mmol) in the presence of CuI(0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.05 mL) at roomtemperature within 30 min. The reaction was poured into a mixturecontaining saturated NH₄Cl/NH₄OH (pH=9.5, 30 mL) and extracted withCH₂Cl₂ (3×30 mL). The combined organic layer was dried over Na₂SO₄ andthe solvent evaporated. The crude was purified on silica gel elutingwith CH₂Cl₂/MeOH/NH₄OH 18:1:0.05 to 15:1:0.05 to 12:1:0.05 to give 368as a white solid (0.146 g, 95% yield). Data for 368: MS (ESI) m/z 1037.1(M+H)⁺; ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.59 (s, 1H), 7.05 (t, J=8Hz, 1H), 6.89–6.84 (m, 2H), 5.02 (m, 2H), 4.37 (d, J=7 Hz, 1H), 4.22 (d,J=2 Hz, 1H), 4.07 (m, 2H), 3.78 (m, 1H), 3.60 (m, 2H), 0.82 (m, 6H).

Synthesis of Triazole 369

This compound was obtained from the reaction of alkyne 173 (0.115 g,0.148 mmol) with azide 424 (0.048 g, 0.192 mmol) in the presence of CuI(0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.02 mL) at roomtemperature within 30 min. The reaction was worked-up as described forthe synthesis of 368 and purified on silica gel eluting withCHCl₃/MeOH/NH₄OH 15:1:0.05 to give 369 as a white solid (0.121 g, 79%yield). Data for 369: MS (ESI) m/z 1037.8 (M+H)⁺; ¹H-NMR (300 MHz,CDCl₃, partial): δ 7.61 (s, 1H), 7.24 (m, 1H), 7.11 (t, J=8 Hz, 1H),6.95 (m, 1H), 5.08 (d, J=4 Hz, 1H), 5.02 (m, 1H), 4.69 (m, 3H), 4.57 (m,1H), 4.42 (d, J=7 Hz, 1H), 4.27 (d, J=3 Hz, 1H), 4.10 (m, 2H), 3.91 (m,1H), 3.65 (m, 2H), 0.88 (m, 6H).

Synthesis of Triazole 370

This compound was obtained from the reaction of alkyne 173 (0.115 g,0.148 mmol) with azide 428 (0.048 g, 0.192 mmol) in the presence of CuI(0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.02 mL) at roomtemperature within 30 min. The reaction was worked-up as described forthe synthesis of 368 and purified on silica gel eluting withCHCl₃/MeOH/NH₄OH 15:1:0.05 to give 370 as a white solid (0.129 g, 84%yield). Data for 370: MS (ESI) m/z 1037.8 (M+H)⁺; ¹H-NMR (300 MHz,CDCl₃, partial): δ 7.62 (s, 1H), 7.23–7.16 (m, 2H), 6.98 (t, J=9 Hz,1H), 5.08–5.04 (m, 2H), 4.72 (m, 3H), 4.44 (d, J=7 Hz, 1H), 4.29 (m,2H), 4.11 (m, 2H), 3.93 (m, 1H), 3.66 (m, 2H), 0.90 (m, 6H).

Example 43 Synthesis of Triazoles 371 and 372

Scheme 66 depicts the synthesis of triazoles 371 and 372. Thesilylethers 429 and 430 were synthesized from the available carboxylicacids, and were transformed into azides 435 and 436. The cycloadditionof 435 and 436 yielded triazoles 371 and 372 respectively.

Synthesis of Silylethers 429 and 430

3-(4-Amino-phenyl)-propionic acid was reduced to the corresponding aminoalcohol as described in the literature (Anhowry et al., J. Chem. Soc.Perkin Trans. 11974, 191–192). The crude amino alcohol was sequentiallyprotected with CBZ- and TBS-groups as described below for compound 437.The crude was purified on silica gel (eluting with EtOAc/flexanes, 1:7)to give compound 429 as colorless oil (about 74% yield, three steps).

(4-Nitro-phenyl)-acetic acid was reduced to the nitro-alcohol asdescribed in the literature (Anhowry et al., J. Chem. Soc. Perkin Trans.11974, 191–192). Catalytic hydrogenation afforded the correspondingamino alcohol. Subsequent CBZ- and TBS-group protection, as describedbelow for compound 437, followed by purification on a silica gel column(eluting with EtOAc/Hexanes, 1:8 to 1:7) gave compound 430 as whitesolid (about 78% yield, 4 steps).

Synthesis of Azides 435 and 436

Silylethers 429 and 430 were converted to azides 435 and 436 using thechemistry reported in the literature (Brickner, S. J. et al. J. Med.Chem. 1996, 39, 673), followed by desilylation using standardconditions.

Synthesis of Triazoles 371 and 372

Triazole 371 was obtained from the reaction of alkyne 173 (0.120 g,0.154 mmol) with azide 435 (0.051 g, 0.185 mmol) in the presence of CuI(0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.02 mL) at roomtemperature within 30 min. The reaction was worked-up as described forthe synthesis of triazole 368 and purified on silica gel (eluting withCH₂Cl₂/MeOH/NH₄OH 15:1:0.05 to 14:1:0.05) to give 371 as a white solid(0.124 g, 76% yield). Data for 371: MS (ESI) m/z 1063.9 (M+H)⁺; ¹H-NMR(300 MHz, CDCl₃, partial): δ 7.63 (s, 1H), 7.32 (d, J=8 Hz, 2H), 7.19(d, J=8 Hz, 2H), 5.05 (m, 2H), 4.72 (m, 3H), 4.45 (d, J=7 Hz, 2H), 4.28(d, J−4 Hz, 1H), 4.15 (m, 2H), 3.92 (m, 1H), 0.90 (m, 6H).

Triazole 372 was obtained from the reaction of alkyne 173 (0.120 g,0.154 mmol) with azide 436 (0.049 g, 0.185 mmol) in the presence of CuI(0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.02 mL) at roomtemperature within 30 min. The reaction was worked-up as described forthe synthesis of triazole 368 and purified on silica gel (eluting withCH₂Cl₂/MeOH/NH₄OH 15:1:0.05 to 14:1:0.05) to give 372 as a white solid(0.116 g, 72% yield). Data for 372: MS (ESI) m/z 1050.0 (M+H)⁺; ¹H-NMR(300 MHz, CDCl₃, partial): δ 7.59 (s, 1H), 7.31 (d, J=8 Hz, 2H), 7.18(d, J=8 Hz, 2H), 5.02 (m, 2H), 4.66 (m, 3H), 4.51 (m, 1H), 4.40 (d, J=6Hz, 2H), 4.24 (m, 1H), 4.10 (m, 2H), 3.61 (m, 2H), 0.86 (m, 6H).

Example 44 Synthesis of Triazole 373

Scheme 67 depicts the synthesis of triazole 373. Trans4-aminocyclohexanol was converted to carbamate 437 prior to furthermanipulation into azide 439. The cycloaddition of 439 with alkyne 173afforded triazole 373.

Synthesis of Carbamate 437

Trans 4-aminocyclohexanol was protected with a CBZ-group as described inthe literature (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673) andprotected with a TBS-group as described in the literature (Green, T. W.;Wuts, P. G. M., Protective Groups in Organic Synthesis, 1991, John Wiley& Sons, Inc., pp 77–83) to give crude compound 437 which was usedwithout further purification.

Synthesis of Azide 439

Carbamate 437 was converted to azide 439 using the chemistry reported inthe literature (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673).

Synthesis of Triazole 373

Triazole 373 was obtained from the reaction of alkyne 173 (0.140 g,0.180 mmol) with azide 439 (0.050 g, 0.210 mmol) in the presence of CuI(0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.05 mL) at roomtemperature within 30 min. The reaction was worked-up as described forthe synthesis of triazole 368 and purified on silica gel (eluting withCH₂Cl₂/MeOH/NH₄OH 14:1:0.075) to give triazole 373 as a white solid(0.135 g, 73% yield). Data for 373: MS (ESI) m/z 1027.8 (M+H)⁺; ¹H-NMR(300 MHz, CDCl₃, partial): δ 7.50 (s, 1H), 5.13 (m, 2H), 4.90 (m, 2H),4.61 (m, 4H), 4.12 (m, 3H), 0.90 (m, 6H).

Example 45 Synthesis of Triazoles 374–377

Scheme 68 depicts the synthesis of triazoles 374–377. The cycloadditionof fluoroaryl azides 440 and 441 with alkynes 173 and 174 providedtriazoles 374–377.

Synthesis of Azides 440 and 441

The azides were synthesized from the substituted anilines using thechemistry reported in the literature (Brickner, S. J. et al. J. Med.Chem. 1996, 39, 673).

Synthesis of Triazole 374

This compound was obtained from the reaction of alkyne 173 (0.250 g,0.318 mmol) with azide 440 (0.090 g, 0.381 mmol) in the presence of CuI(0.031 g, 0.150 mmol) in THF (10 mL) and Hunig's base (0.1 mL) at roomtemperature within 30 min. The reaction was worked-up as described forthe synthesis of 368 and purified on silica gel eluting withCH₂Cl₂/MeOH/NH₄OH 15:1:0.05 to give 374 as a white solid (0.294 g, 90%yield). Data for 374: MS (ESI) m/z 1023.7 (M+H)⁺; ¹H-NMR (300 MHz,CDCl₃, partial): δ 7.55 (s, 1H), 7.30 (m, 2H), 6.97 (t, J=9 Hz, 2H),4.99 (m, 2H), 4.36 (d, J=7 Hz, 1H), 4.22 (d, J=3 Hz, 1H), 4.07 (m, 2H),3.84 (m, 1H), 3.59 (m, 2H), 0.82 (m, 6H).

Synthesis of Triazole 375

This compound was obtained from the reaction of alkyne 174 (0.150 g,0.187 mmol) with azide 440 (0.068 g, 0.288 mmol) in the presence of CuI(0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.05 mL) at roomtemperature within 30 min. The reaction was worked-up as described forthe synthesis of 368 and purified on silica gel eluting withCH₂Cl₂/MeOH/NH₄OH 15:1:0.05 to 12:1:0.05 to give 375 as a white solid(0.139 g, 72% yield). Data for 375: MS (ESI) m/z 1037.7 (M+H)⁺; ¹H-NMR(300 MHz, CDCl₃): δ 7.46 (s, 1H), 7.27 (m, 2H), 6.97 (m, 2H), 5.05 (d,J=5 Hz, 1H), 4.96 (m, 1H), 4.65 (m, 4H), 4.38 (d, J=7 Hz, 1H), 4.22 (d,J=3 Hz, 1H), 4.05 (m, 2H), 3.87 (m, 1H), 3.56 (m, 2H), 0.83 (m, 6H).

Synthesis of Triazole 376

This compound was obtained from the reaction of alkyne 173 (0.140 g,0.180 mmol) with azide 441 (0.053 g, 0.210 mmol) in the presence of CuI(0.023 g, 0.111 mmol) in THF (5 mL) and Hunig's base (0.05 mL) at roomtemperature within 30 min. The reaction was worked-up as described forthe synthesis of 368 and purified on silica gel eluting withCH₂Cl₂/MeOH/NH₄OH 15:1:0.05 to 15:1:0.1 to give 376 as a white solid(0.183 g, 98% yield). Data for 376: MS (ESI) m/z 1041.7 (M+H)⁺; ¹H-NMR(300 MHz, CDCl₃, partial): <7.61 (s, 1H), 7.48 (m, 1H), 7.13 (m, 1H),7.00 (m, 1H), 5.07 (m, 2H), 4.72 (m, 3H), 4.43 (d, J=7 Hz, 1H), 4.29 (m,2H), 4.14 (m, 2H), 3.85 (m, 1H), 3.66 (m, 2H), 0.88 (m, 6H).

Synthesis of Triazole 377

Alkyne 174 (150 mg, 0.187 mmol) and azide 441 (52.3 mg, 0.206 mmol) weretreated with copper (I) iodide under similar conditions as reportedabove for the synthesis of triazole 361 to afford 170 mg of 377. Datafor 377: MS (ESI) m/z 528.5 (M+2H)²⁺, 1055.7 (M+H)⁺; ¹H NMR (300 MHz,CDCl₃, partial): δ 7.51 (s, 1H), 7.49–7.42 (m, 1H), 7.14 (dd, J=9, 9 Hz,1H), 6.99–6.96 (m, 1H), 5.13 (d, J=5 Hz, 1H), 5.07–5.02 (m, 1H), 4.44(d, J=7 Hz, 1H), 3.95 (dd, J=6, 3 Hz, 1H), 3.48 (s, 3H), 3.34 (s, 3H),3.03 (t, J=9 Hz, 1H), 0.92–0.87 (m, 6H).

Example 46 Synthesis of Triazole 378

Scheme 69 depicts the synthesis of triazole 378. The reductive aminationreaction of 4-iodobenzylamine and quinoline-4-carboxaldehyde yieldedamine 442 which was converted to the BOC derivative 443.Palladium-catalyzed conversion of iodide 443 to the correspondingpinacol boronate ester was followed by in situ Suzuki coupling withiodoaryl azide 253 to yield azide 444. The cycloaddition of 444 withalkyne 173 gave triazole 378.

Synthesis of Amine 442

A solution of 4-iodobenzylamine (0.93 g, 4.0 mmol) in methanol (10 mL)was treated with quinoline-4-carboxaldehyde (0.50 g, 3.2 mmol), aceticacid (0.2 mL) and sodium triacetoxyborohydride (1.7 g, 8.0 mmol), andthe mixture was stirred under argon at 23° C. for 3 h. The reactionmixture was diluted with ethyl acetate (150 mL), washed with saturatedaqueous sodium bicarbonate (2×100 mL), dried (Na₂SO₄), and evaporated toprovide iodide 442 (0.83 mg, 69% yield) as a yellow oil. Data for 442:MS (ESI) m/z 375 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 8.80 (d, J=5 Hz, 1H),8.07 (d, J=8 Hz, 1H), 7.94 (d, J=8 Hz, 1H), 7.65–7.58 (m, 1H), 7.59 (d,J=8 Hz, 2H), 7.52–7.42 (m, 1H), 7.37 (d, J=5 Hz, 1H), 7.05 (d, J=8 Hz,2H), 4.13 (s, 2H), 3.76 (s, 2H).

Synthesis of Iodide 443

A solution of iodide 442 (0.66 g, 1.8 mmol) in methylene chloride (15mL) was treated with di-tert-butyl dicarbonate (0.42 mL, 3.2 mmol), andheated to reflux for 0.5 h. The reaction mixture was evaporated, and theresidue purified by flash chromatography (SiO₂, 15–50% ethylacetate/methylene chloride) to provide iodide 443 (0.72 g, 86% yield) asa colorless oil. Data for 443: MS (ESI) m/z 475 (M+H)⁺; ¹HNMR (300 MHz,CDCl₃): δ 8.85 (d, J=4 Hz, 1H), 8.12 (d, J=8 Hz, 1H), 7.98–7.82 (m, 1H),7.72–7.66 (m, 1H), 7.61 (d, J=8 Hz, 2H), 7.54–7.48 (m, 1H), 7.16 (d, J=5Hz, 1H), 6.98–6.85 (m, 2H), 4.88–4.80 (m, 2H), 4.43–4.29 (m, 2H),1.49–1.42 (m, 9H).

Synthesis of Azide 444

A solution of iodide 443 (0.22 g, 0.46 mmol) in dioxane (2.5 mL) wastreated with triethylamine (0.19 mL, 1.4 mmol), pinacol borane (0.090mL, 0.61 mmol), and Pd(dppf)Cl₂ (10 mg, 0.012 mmol) and heated to 80° C.for 3 h. The reaction mixture was cooled to room temperature, dilutedwith ethanol (0.83 mL) and H₂O (0.83 mL), treated with potassiumcarbonate (0.19 g, 1.4 mmol), azide 253 (0.17 g, 0.46 mmol), andPd(dppf)Cl₂ (10 mg, 0.012 mmol), and heated to 80° C. for 3 h. Thereaction mixture was cooled to room temperature, diluted with methylenechloride (50 mL), washed with saturated aqueous sodium bicarbonate (2×50mL), dried (Na₂SO₄), and evaporated. Flash chromatography (SiO₂, 50–100%ethyl acetate/methylene chloride) provided azide 444 (0.18 g, 67% yield)as a yellow oil. Data for 444: ¹HNMR (300 MHz, CD₃OD/CDCl₃): δ 8.76 (d,J=5 Hz, 1H), 8.04–8.00 (m, 2H), 7.77–7.69 (m, 1H), 7.62–7.43 (m, 8H),7.33–7.25 (m, 1H), 4.89–4.83 (m, 1H), 4.28 (s, 2H), 4.22–4.12 (m, 1H),3.94 (s, 2H), 3.92–3.88 (m, 1H), 3.79–3.72 (m, 1H), 3.62–3.56 (m, 1H).

Synthesis of Triazole 378

A solution of azide 444 (0.090 g, 0.15 mmol) in dichloromethane (4.0 mL)was treated with trifluoroacetic acid (4.0 mL) and stirred at 23° C. for1 h. The solvent was removed under reduced pressure, and the residuedissolved in chloroform (100 mL) and washed with 10% aqueous potassiumcarbonate (100 mL), dried (Na₂SO₄), and evaporated to provide 50 mg ofdeprotected amine as an orange solid.

A solution of this crude amine (0.0430 g, 0.089 mmol) and alkyne 173(0.056 g, 0.071 mmol) in tetrahydrofuran (1.5 mL) was treated withN,N-diisopropylethylamine (0.015 mL, 0.089 mmol) and copper (I) iodide(2.0 mg, 0.0089 mmol) and stirred under argon at 23° C. for 1 h. Thereaction mixture was diluted with saturated aqueous ammonium hydroxide(10 mL) and extracted with dichloromethane (3×20 mL). The combinedorganic fractions were dried (Na₂SO₄) and evaporated, and the residuepurified by preparative thin-layer chromatography (PTLC, SiO₂, ammoniumhydroxide/methanol/ethyl acetate/dichloromethane 0.5:10:15:74.5) toprovide 378 (44 mg, 48% yield) as a white powder. Data for 378: MS (ESI)m/z 1270 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.89 (d, J=5 Hz,1H), 8.12 (d, J=9 Hz, 1H), 8.06 (d, J=8 Hz, 1H), 7.72–7.68 (m, 1H), 7.62(s, 1H), 7.19–7.17 (m, 1H), 4.30 (s, 2H), 3.96 (s, 2H), 3.33 (s, 3H),2.33 (s, 3H), 2.26 (s, 3H), 0.88–0.86 (m, 6H).

Example 47 Synthesis of Triazole 379

Scheme 70 depicts the synthesis of triazole 379. Azide 300 was convertedto hydroxyamidine 445 which was subsequently cyclized withtriethylorthoformate to oxadiazole azide 446. The cycloaddition of 446with alkyne 173 yielded triazole 379.

Synthesis of Azide 446

A solution of azide 300 (300 mg, 1.1 mmol) in ethanol (5.5 mL) wastreated with potassium carbonate (152 mg, 1.1 mmol) and hydroxylaminehydrochloride (153 mg, 2.2 mmol) and refluxed for 3 h. The reaction wascooled to 23° C. and the solvent was evaporated in vacuo. The crudehydroxyamidine was added to triethylorthoformate (5.5 mL) and thereaction was refluxed for 2 h, cooled to 23° C. and stirred for 48 h,and then refluxed for 1 h. The reaction was then cooled to 23° C. anddiluted with ethyl acetate (20 mL). The organic layer was washed with 1M hydrochloric acid (20 mL). Drying (Na₂SO₄) and evaporation providedoxadiazole azide 446 (80 mg, 0.26 mmol, 24% yield). Data for 446: ¹HNMR(300 MHz, CDCl₃): δ 8.80 (s, 1H), 8.12 (t, J=8 Hz, 1H), 7.66 (dd, J=13,2 Hz, 1H), 7.43 (dd, J=9, 2 Hz, 1H), 4.91–4.81 (m, 1H), 4.17–4.11 (m,1H), 3.93 (dd, J=9, 6 Hz, 1H), 3.77 (dd, J=4, 13, 1H), 3.63 (dd, J=4,13, 1H).

Synthesis of Triazole 379

A solution of alkyne 173 (135 mg, 0.17 mmol) and azide 446 (65 mg, 0.21mmol) in tetrahydrofuran (1.3 mL) was treated with diisopropylethylamine(0.037 mL, 0.21 mmol) and then degassed by application of vacuum andintroduction of argon. Copper (I) iodide (4 mg, 0.021 mmol) was added,and the reaction was again degassed. The reaction was stirred underargon at 23° C. for 1 h, and then purified by flash chromatography(SiO₂, ammonium hydroxide/methanol/dichloromethane (0.05:1:12)) toprovide 379 (153 mg, 0.14 mmol, 82% yield) as a white powder. Data for379: MS (ESI) m/z 1091.8 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.80(s, 1H), 8.18–8.136 (m, 1H), 7.69 (s, 1H), 7.65 (dd, J=13, 2, 1H),7.37–7.33 (m, 1H), 4.82–4.80 (m, 1H), 4.67 (dd, J=10, 2 Hz, 1H), 3.41(s, 3H), 0.98–0.93 (m, 6H).

Example 48 Synthesis of Triazole 380

The required 3,5-difluoroaryl oxazolidinone azide was synthesized from3,5-difluoroaniline using the chemistry reported in the literature(Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673).

Alkyne 328 (70 mg, 86 μmol), the above azide (33 mg, 129 μmol), and CuI(2 mg, 8 μmol) were reacted under the conditions described for thesynthesis of triazole 228 to afford triazole 380 as a white solid (92.6mg, 85 μmol). Data for 380: MS (ESI) m/z 543 (M+2H)²⁺; ¹HNMR (300 MHz,CDCl₃, partial): δ 7.99 (bs, 1H), 7.42 (s, 1H). 7.00–6.92 (m, 2H), 6.51(tt, J=9, 2 Hz, 1H), 5.06–4.99 (m, 1H), 4.94 (d, J=6 Hz, 1H), 4.66 (d,J=5 Hz, 2H), 4.59 (dd, J=9, 2 Hz, 1H), 4.38 (d, J=7 Hz, 1H), 4.22 (dd,J=6, 2 Hz, 1H), 4.10 (t, J=8 Hz, 1H), 4.10–4.00 (m, 1H), 3.87–3.82 (m,2H), 3.61–3.57 (m, 2H), 3.53–3.41 (m, 2H), 3.33 (s, 3H), 3.16 (dd, J=10,4 Hz, 1H), 2.96 (t, J=10 Hz, 1H), 2.85–2.73 (m, 5H), 2.31 (s, 3H), 2.19(s, 3H), 0.83 (d, J=6 Hz, 3H), 0.81 (t, J=7 Hz, 3H).

Example 49 Synthesis of Triazoles 381 and 382

Scheme 71 depicts the synthesis of triazoles 381 and 382. Amine 171 wasconverted to carbamate 447 prior to cycloaddition with azide 158 toafford triazole 381. Amine 171 was demethylated to yield amine 448,which was subsequently transformed to carbamate 449 and ultimatelytriazole 382.

Synthesis of Carbamate 447

To a stirred solution of 171 (0.72 g, 1.0 mmol) in CH₂Cl₂ (10 mL) andHunig's base (1 mL), was added dropwise a CH₂Cl₂ solution of 4-butynylchlorofomate (135 mg, 1.01 mmol in 2 mL). The mixture was stirred at rtfor 16 h, then diluted to 50 mL with CH₂Cl₂ and washed with sat. aq.NaHCO₃ (50 mL) and brine (25 mL). The organic fraction was dried overK₂CO₃, filtered and concentrated to give 0.9 g of a foam which waspurified by silica gel chromatography (25 mm×6″ column eluted with 50:1CH₂Cl₂/2N NH₃ in MeOH) to afford carbamate 447 as a white solid (0.68 g,0.83 mmol). Data for 447: MS (ESI) m/z 815 (M+H)⁺; ¹HNMR (300 MHz,CDCl₃, partial): δ 8.72 (bs, 1H), 5.07 (d, J=4 Hz, 1H), 4.95 (d, J=7 Hz,1H), 3.32 (s, 3H), 2.90 (s, 3H), 2.31 (s, 3H), 1.34–1.27 (m, 8H),1.27–1.15 (m, 10H), 1.10–0.99 (m, 9H), 0.92–0.84 (m, 6H).

Synthesis of Triazole 381

Alkyne 447 (60 mg, 72 μmol), azide 158 (35 mg, 108 μmol), and CuI (2 mg,8 μmol) were reacted under the conditions described for the synthesis ofcompound 228 to afford triazole 381 as a white solid (67 mg, 65 μmol).Data for 381: MS (ESI) m/z 1137 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 8.9 (bs, 1H), 7.63 (s, 1H), 7.05–6.92 (m, 1H), 6.82 (t, J=9 Hz, 1H),5.10–4.90 (m, 2H), 4.80–4.00 (m, 7H), 3.90–3.81 (m, 3H), 3.70–3.58 (m,2H), 3.41–3.25 (m, 3H) 3.20 (pent, J=6, 1H), 3.10–2.96 (m, 4H),2.92–2.38 (m 5H), 2.29 (s, 3H), 2.10–1.40 (m, 51H), 1.25–1.04 (m, 15H),0.93 (d, J=8, 3H), 0.94–0.83 (m, 6H).

Synthesis of Amine 448

To a stirred solution of desmethyl azithromycin 171 (10.0 g, 13.6 mmol)in methanol (200 mL) was added sodium methoxide (1.33 g, 25 mmol). Themixture was cooled to 0° C. prior to the addition of iodine (3.55 g, 14mmol). The mixture was stirred at 0° C. for 1.5 h, then warmed to rtover 1 h. The reaction mixture was poured into ice water (1 L) and thesolution was adjusted to pH 12 by addition of KOH which led to theprecipitation of a white solid. After sitting at 0° C. for 1 h, thesolid was filtered to give 7.2 g of crude product which wasrecrystallized from boiling methanol to give 3.8 g of product as whitecrystals. Data for 448: MS (ESI) m/z 361.24 (M+2H)²⁺; ¹HNMR (300 MHz,CDCl₃, partial): δ 8.48 (bs, 1H), 5.18 (bs, 1H), 4.95 (d, J=4 Hz, 1H),4.60 (dd, J=10, 2 Hz, 1H), 4.30 (d, J=8 Hz, 1H), 4.18 (dd, J=5, 2 Hz,1H), 4.06–3.96 (m, 1H), 3.60–3.48 (m, 3H), 3.27 (s, 3H) 2.28 (s, 3H).

Synthesis of Carbamate 449

3′-N-bis-demethyl azithromycin 448 (180 mg, 0.25 mmol) was treated with4-butynyl chlorofomate (35 mg, 0.25 mmol) under the same conditionsdescribed for the synthesis of 447 to afford carbamate 449 as a whitesolid (157 mg, 0.19 mmol). Data for 449: MS (ESI) m/z 1123 (M+H)⁺; ¹HNMR(300 MHz, CDCl₃, partial): δ 8.18 (bs, 1H), 4.92 (d, J=4 Hz, 1H), 4.78(d, J=4 Hz, 1H), 4.39 (d, J=6 Hz, 1H), 4.15 (t, J=7 Hz, 2H), 4.05–3.92(m, 1H), 3.28 (s, 3H), 2.30 (s, 3H), 1.68 (d, J=8 Hz, 1H), 1.51 (dd,J=8, 3 Hz, 1H), 1.28–1.12 (m, 8H), 1.27–1.15 (m, 10H), 1.05 (d, J=7 Hz,3H), 1.00 (s, 3H), 0.91 (d, J=7 Hz, 3H), 0.92–0.84 (m, 6H).

Synthesis of Triazole 382

Alkyne 449 (40 mg, 49 μmol), azide 158 (24 mg, 73 μmol), and CuI (2 mg,8 μmol) were reacted under the conditions described for the synthesis ofcompound 228 to afford triazole 382 as a white solid (67 mg, 65 μmol).Data for 382: MS (ESI) m/z 1135 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 8.30 (bs, 1H), 7.54 (s, 1H), 7.11–7.02 (m, 2H), 6.82–6.70 (m, 2H),5.41 (d, J=5 Hz, 1H), 5.05–4.90 (m, 2H), 4.68 (d, J=4 Hz, 1H), 4.59 (d,J=6 Hz, 1H), 3.28 (s, 3H), 2.25 (s, 3H), 1.69 (d, J=8 Hz, 1H), 1.31–1.01(m, 15H), 0.95 (d, J=8, 3H), 0.80 (t, J=8, 3H).

Example 50 Synthesis of Triazoles 383 and 384

Scheme 72 depicts the synthesis of triazoles 383 and 384.4-Nitrobenzenesulfonyl chloride was convereted to sulfonamide 450 whichwas manipulated to carbamate 452 by standard chemistry. Oxazolidinoneformation followed by azide formation gave 455. The cycloaddition of 455with alkynes 173 and 174 rendered triazoles 383 and 384 respectively.

Synthesis of Azide 455

4-Nitrobenzenesulfonyl chloride (2.22 g, 10 mmol) was added to asolution of dimethylamine (10 mL, 2.0 M in THF, 20 mmol) at 0° C. Thereaction was stirred at 0° C. for 1 h and then at room temperature foradditional 1 h. The THF was removed under vacuum, more water was added,and the precipitate was collected by filtration and dried to afford 450(2.20 g, 96% yield). Data for 450: ¹HNMR (300 MHz, CDCl₃-CD₃OD): δ 8.33(d, J=9 Hz, 2H), 7.90 (d, J=9 Hz, 2H), 2.70 (s, 6H).

To a solution of sulfonamide 450 (2.2 g, 9.6 mmol) in methanol (30 mL)was added 10% Pd—C (0.25 g) and the resulting mixture was stirred atroom temperature for 6 h under 1 atm hydrogen atmosphere. The Pd—C wasremoved by filtration on celite. The filtered solution was evaporated toprovide 451 (1.8 g, 94% yield) as a white solid. Data for 451: ¹HNMR(300 MHz, CDCl₃): δ 7.43 (d, J=9 Hz, 2H), 6.59 (d, J=9 Hz, 2H), 2.53 (s,6H).

Benzyl chloroformate (1.4 mL, 9.6 mmol) was added dropwise to a solutionof aniline 451 (1.60 g, 8.0 mmol), and NaHCO₃ (2.70 g, 21 mmol) in amixture of THF (5 mL) and water (3 mL) at 0° C. After stirring at 0° C.for 2 h and room temperature for 4 h, the reaction mixture was dilutedwith ethyl acetate (30 mL). The organic layer was washed with brine(3×50 mL), dried (MgSO₄) and concentrated to provide 2.35 g of whitesolid 452 in a yield of 93%. Data for 452: ¹HNMR (300 MHz, CDCl₃): δ7.79 (d, J=9 Hz, 2H), 7.64 (d, J=9 Hz, 2H), 7.50–7.45 (m, 5H), 7.02 (brs, 1H), 5.30 (s, 2H), 2.76 (s, 6H).

To a solution of CBZ-protected amine 452 (1.0 g, 3 mmol) in THF (20 mL)was added n-BuLi (3.3 mL, 1.6 M in hexane, 5.28 mmol) at −78° C. and themixture was stirred for 30 min. (R)-(−)-Glycidyl butyrate (0.53 mL, 3.75mmol) was added, the reaction was stirred at −78° C. for 3 h and wasthen warmed to room temperature and stirred overnight. The reaction wascarefully quenched with saturated NH₄Cl and extracted with EtOAc. Theorganic phase was washed with brine, dried (MgSO₄) and concentrated. Thecrude product was recrystallized from ethyl acetate to give alcohol 453as a white crystalline solid (0.45 g, 50% yield). Data for 453: MS (ESI)m/z 300.9 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.83 (d, J=9 Hz, 2H), 7.78(d, J=9 Hz, 2H), 4.86 (m, 1H), 4.19–4.07 (m, 3H), 3.85 (dd, J=4, 13 Hz,1H), 2.75 (s, 6H).

To a solution of alcohol 453 (200 mg, 0.67 mmol) and Et₃N (101 mg, 1.0mmol) in CH₂C₂ (5 mL) was added methanesulfonyl chloride (92 mg, 0.80mmol) at 0° C. The mixture was stirred at room temperature for 30 min.The CH₂Cl₂ solution was washed with brine, dried (MgSO₄), concentratedand crystallized from EtOAc to afford mesylate 454 (238 mg, 94% yield).Data for 454: MS (ESI) m/z 378.9 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.80(d, J=9 Hz, 2H), 7.73 (d, J=9 Hz, 2H), 4.98 (m, 1H), 4.54 (dd, J=4, 12Hz, 1H), 4.46 (dd, J=4, 12 Hz, 1H), 4.23 (t, J=9 Hz, 1H), 4.04 (dd, J=6,9 Hz, 1H), 3.11 (s, 3H), 2.70 (s, 6H).

A mixture of 454 (200 mg, 0.52 mmol) and sodium azide (137 mg, 2.11mmol) in DMF (4 mL) was heated at 80° C. for 3 h. The reaction mixturewas diluted with EtOAc, washed with brine, dried (MgSO₄), concentratedand crystallized from EtOAc/MeOH to afford azide 455 (149 mg, 88%yield). Data for 455: ¹HNMR (300 MHz, DMSO): δ 7.72 (d, J=9 Hz, 2H),7.67 (d, J=9 Hz, 2H), 4.83 (m, 1H), 4.11 (t, J=9 Hz, 1H), 3.77–3.58 (m,3H), 2.58 (s, 6H).

Synthesis of Triazole 383

A mixture of alkyne 173 (118 mg, 0.15 mmol), azide 455 (54 mg, 0.165mmol) and copper (I) iodide (28.5 mg, 0.15 mmol) in THF (5 mL) wasrepeatedly degassed and flushed with argon. Hunig's base (0.26 mL) wasintroduced and the mixture stirred at room temperature for 12 h. Thereaction mixture was poured into saturated NH₄Cl (30 mL) and stirred for15 minutes. The mixture was extracted with CH₂Cl₂, washed with brine,dried over MgSO₄ and concentrated. Chromatography on silica gel(25:1:0.05 CH₂Cl₂/MeOH/NH₃-H₂O as eluant) provided 383 (145 mg, 87%yield) as a white foam. Data for 383: MS (ESI) m/z 1112.7 (M+H)⁺, 557.1(100%); ¹HNMR (300 MHz, CDCl₃, partial): δ 7.70 (d, J=9 Hz, 2H), 7.61(s, 1H), 7.60 (d, J=9 Hz, 2H), 3.32 (s, 3H), 2.66 (s, 6H), 2.28 (s, 3H),2.26 (s, 3H), 0.87 (t, J=8 Hz, 3H).

Synthesis of Triazole 384

A mixture of alkyne 174 (120 mg, 0.15 mmol), azide 445 (54 mg, 0.165mmol) and copper (I) iodide (28.5 mg, 0.15 mmol) in THF (5 mL) wasrepeatedly degassed and flushed with argon. Hunig's base (0.26 mL) wasintroduced and the mixture stirred at room temperature for 12 h. Thereaction mixture was poured into saturated NH₄Cl (30 mL) and stirred for15 minutes. The mixture was extracted with CH₂Cl₂, washed with brine,dried over MgSO₄ and concentrated. Chromatography on silica gel(25:1:0.05 CH₂Cl₂MeOH/NH₃-H₂O as eluant) provided 384 (150 mg, 89%yield) as a white foam. Data for 384: MS (ESI) m/z 1126.7 (M+H)⁺, 564.1(100%); ¹HNMR (300 MHz, CDCl₃, partial): δ 7.74 (d, J=9 Hz, 2H), 7.60(d, J=9 Hz, 2H), 7.52 (s, 1H), 3.33 (s, 3H), 2.68 (s, 6H), 2.32 (s, 3H),2.23 (s, 3H), 0.89 (t, J=8 Hz, 3H).

Example 51 Synthesis of Triazoles 385–389

Scheme 73 depicts the synthesis of triazole 385.3-Chloro-4-methoxyaniline was converted to carbamate 456 which wassubsequently parlayed to azide 459. The cycloaddition of 459 with alkyne173 afforded triazole 385. The same chemistry depicted in Scheme 73 wasused to synthesize triazoles 386–389 from the appropriate anilines.

Synthesis of Azide 459

Sodium bicarbonate (2.69 g, 25.4 mmol) was dissolved in water (22 mL)and (45 mL) acetone. To this solution p-anisidine (2.0 g, 12.7 mmol) wasadded. The mixture was cooled to 0° C., and benzyl chloroformate (1.81mL, 12.70 mmol) was added. The mixture was stirred 5 min at 0° C., thecold bath removed, and then stirring was continued at room temperatureovernight (˜16 hours). The mixture was evaporated, and partitioned witha 1:1 mixture of ethyl acetate and water. The organic layer was washedwith water, and then brine. The organic layer was dried with Na₂SO₄, andevaporated to yield carbamate 456 (3.20 g, 86% yield) of suitable purityfor use in subsequent reactions. Data for 456: ¹HNMR (300 MHz, CDCl₃): δ7.50 (s, 1H), 7.30 (m, 5H), 7.10 (d, J=5 Hz, 1H), 6.80 (d, J=8 Hz, 1H),5.15 (s, 2H), 3.84 (s, 3H).

Carbamate 456 (1.0 g, 3.43 mmol) was dissolved in 50 mL tetrahydrofuran,and the solution cooled to −78° C. n-Butyllithium (2.5 M in hexane, 2.1mL, 3.43 mmol) was added slowly, and the mixture allowed to stir for 45min at −78° C. R-Glycidyl butyrate (0.5 mL, 3.5 mmol) was added, and themixture was stirred for 1 h at −78° C. The bath was removed and thereaction allowed to stir overnight at room temperature. The reaction wasquenched with 10 mL saturated ammonium chloride solution, andpartitioned with ethyl acetate and water. The aqueous layer wasextracted thrice with ethyl acetate, and the combined organic layer waswashed with brine, dried (Na₂SO₄), and evaporated to yield alcohol 457(0.5 g, 63% yield) of suitable purity for use in subsequent reactions.Data for 457: ¹HNMR (300 MHz, CDCl₃): δ 7.49 (s, 1H), 7.35 (m, 1H), 6.84(d, J=5 Hz, 1H), 4.71 (m, 1H), 3.95 (m, 2H).

Alcohol 457 (0.5 g, 1.94 mmol) was dissolved in 5 mL methylene chloride,and the mixture cooled to 0° C. Triethylamine (0.54 mL, 3.88 mmol) wasadded, followed by methanesulfonyl chloride (0.2 mL, 2.72 mmol). Themixture was allowed to warm to room temperature and stirred for 1 hr.Methylene chloride (10 mL) was added, and the mixture washed twice with1N HCl, then twice with 10% aqueous sodium carbonate, and then brine.The organic phase was dried (Na₂SO₄), and evaporated to yield mesylate458 (0.60 g, 92% yield).

A solution of mesylate 458 (0.60 g, 1.79 mmol) in dimethylformamide (5mL) was treated with sodium azide (0.46 g, 7.15 mmol) and the mixtureheated to 80° C. for 5 h. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate (50 mL), and washed with brine(2×50 mL). Drying (Na₂SO₄), and evaporation provided azide 459 (0.45 g,90% yield) as a yellow solid of suitable purity for use in subsequentreactions. Data for 459: ¹HNMR (300 MHz, CDCl₃): δ 7.50 (s, 1H), 7.35(dd, J=2, 5 Hz, 1H), 6.87 (d, J=9 Hz, 1H), 4.75 (m, 1H), 4.0 (t, J=9 Hz,1H), 3.75 (dd, J=9, 13 Hz, 1H), 3.52 (dd, J=5, 13 Hz, 1H).

Synthesis of Triazole 385

A solution of but-3-ynyl-methyl-amino azithromycin 173 (100 mg, 0.127mmol) in tetrahydrofuran (5 mL) was treated with azide 459 (53.0 mg,0.19 mmol), N,N-diisopropylethylamine (0.026 mL, 0.15 mmol) and copper(I) iodide (0.018 g, 0.095 mmol), and the mixture was stirred underargon at room temperature for 16 h. The reaction mixture was dilutedwith ethyl acetate (50 mL), and washed with brine (2×50 mL). The organicphase was dried and evaporated. The residue was purified by preparativethin layer chromatography (using 80% CH₂Cl₂, 20% MeOH, 1% NH₄OH aseluant) to provide triazole 385 (64 mg, 50% yield) as a white solid.Data for 385: ¹HNMR (300 MHz, CDCl₃, partial): δ 7.60 (s, 1H), 7.40 (s,1H), 7.10 (s, 1H), 6.80 (d, J=3 Hz, 1H), 4.95 (m, 1H), 4.60 (m, 1H),4.40 (m, 1H), 4.20 (m, 1H), 4.0 (m, 1H), 3.50 (m, 1H), 3.20 (s, 2H).

Synthesis of Triazoles 386–389

The azides required for the synthesis of triazoles 386–389 weresynthesized from the appropriate amines using the chemistry reported inthe literature (Brickner, S. J. et al. J. Med. Chem. 1996, 39, 673). Theazides were treated with alkyne 173, using the conditions reported abovefor the synthesis of triazole 385, to afford the targets 386–389.

Data for 386: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.50 (s, 1H), 5.0 (s,1H), 4.80 (m, 1H), 4.60 (m, 2H), 4.47 (m, 2H), 3.98–4.20 (m, 5H), 3.60(m, 2H), 3.25 (d, J=6 Hz, 3H), 2.20 (m, 3H).

Data for 387: ¹H-NMR (300 MHz, CDCl₃, partial): δ 7.46 (s, 1H), 7.37 (d,J=2 Hz, 2H), 7.20 (m, 2H), 5.10 (s, 1H), 5.00 (m, 2H), 4.70 (m, 2H),4.45 (d, J=3 Hz, 1H), 4.20 (s, 1H), 4.15 (m, 3H).

Data for 388: ¹H-NMR (300 MHz, CDCl₃, partial): δ 9.0 (s, 1H), 7.50 (m,4H), 5.0 (m, 2H), 4.70 (m, 3H), 4.30 (d, J=2 Hz, 1H), 4.20 (s, 1H), 4.10(m, 1H), 4.0 (m, 1H), 3.98 (m, 1H), 3.60 (m, 2H), 3.20 (m, 3H), 2.98 (t,J=7 Hz, 1H).

Data for 389: ¹H-NMR (300 MHz, CDCl₃, partial): δ 9.20 (s, 1H), 7.50 (s,1H), 7.30 (m, 2H), 6.80 (m, 1H), 5.10 (d, J=5 Hz, 1H), 4.98 (m, 1H),4.80 (d, J=3 Hz, 1H), 4.60 (m, 2H), 4.30 (d, J=2 Hz, 1H), 4.20 (s, 1H),4.0 (m, 2H), 3.80 (s, 3H), 3.60 (m, 2H), 3.27 (s, 3H), 3.11 (app t, J=7Hz, 1H).

Example 52 Synthesis of Triazole 390

Scheme 74 depicts the synthesis of triazole 390. The cycloaddition ofdibromo hydroxyformimine and allyl alcohol provided bromo isoxazoline460 which was then converted into alcohol 461. The alcohol of 461 wastransformed to the azide 462 which underwent cycloaddition to alkyne 173to afford triazole 390.

Synthesis of Isoxazoline 460

A mixture of dibromo hydroxyformimine (1 g, 4.93 mmol), allyl alcohol(1.68 mL, 24.7 mmol), NaHCO₃ (1.58 g, 18.7 mmol) in 1.5 mL water and 18mL ethyl acetate was stirred over night at room temperature. The mixturewas then poured into 20 mL of water and extracted with ethyl acetate(2×20 mL). The combined organic extract was washed with brine (10 mL),dried (Na₂SO₄) and evaporated, yielding 460 (828 mg, 93%). Data for 460:¹HNMR (300 MHz, CDCl₃): δ 4.80–4.65 (m, 1H), 3.85–3.74 (m, 1H),3.61–3.52 (m, 1H), 3.22–3.05 (m, 2H), 1.95–1.75 (br s, 1H).

Synthesis of Alcohol 461

To a solution of 1-butanol (5.1 mL, 55.6 mmol) in 25 mL DMSO was added a2.5 M n-BuLi solution in hexanes (3.9 mL, 9.72 mmol). The mixture wasstirred at room temperature for 20 min, then a solution of 460 (500 mg,2.78 mmol) in 2 mL DMSO was added. The mixture was stirred at roomtemperature for 3 h, poured into 50 mL water/ice and extracted withethyl acetate (3×40 mL). The combined organic extract was washed withwater (4×20 mL), brine (20 mL), dried (Na₂SO₄) and evaporated. Theresidue was purified by flash-chromatography (eluant: hexanes-ethylacetate 2:1) yielding 461 (165 mg, 34%). Data for 461: ¹HNMR (300 MHz,CDCl₃): δ 4.69–4.60 (m, 1H), 4.09–4.00 (m, 2H), 3.78–3.69 (m, 1H),3.59–3.51 (m, 1H), 2.99–2.78 (m, 2H), 1.68–1.55 (m, 2H), 1.40–1.25 (m,2H), 0.90–0.82 (m, 3H).

Synthesis of Azide 462

To a solution of 461 (165 mg, 0.95 mmol) in 3 mL dichloromethane wasadded Et₃N (0.24 mL, 1.72 mmol) followed by MsCl (0.089 mL, 1.14 mmol)at 0° C. The mixture was stirred at 0° C. for 1 h, poured into 10 mLwater/ice and extracted with dichloromethane (2×10 mL). The combinedorganic extract was washed with water (2×10 mL), brine (10 mL), dried(Na₂SO₄) and evaporated. The residue was dissolved in 3 mL DMF, NaN₃(124 mg, 1.91 mmol) was added, and the mixture was stirred at 80° C. for2 h. The mixture was poured into 10 mL water/ice and extracted withethyl acetate (2×10 mL). The combined organic extract was washed withwater (2×10 mL), brine (10 mL), dried (Na₂SO₄) and evaporated. Theresidue was purified by flash-chromatography (eluant: hexanes-ethylacetate 3:1) yielding 462 (155 mg, 82%). Data for 462: ¹HNMR (300 MHz,CDCl₃): δ 4.98–4.85 (m, 1H), 4.31–4.25 (m, 2H), 3.72–3.51 (m, 2H),3.25–3.15 (m, 1H), 3.05–2.91 (m, 1H), 1.92–1.81 (m, 2H), 1.62–1.50 (m,2H), 1.15–1.05 (m, 3H).

Synthesis of Triazole 390

To a solution of alkyne 173 (150 mg, 0.191 mmol) in 6 mL acetonitrilewas added 462 (37.8 mg, 0.191 mmol), 2,6-lutidine (0.025 mL, 0.209 mmol)and CuI (18.2 mg, 0.095 mmol). The mixture was stirred over night atroom temperature, then poured into 10 mL 5% aqueous NH₃/ice andextracted with CH₂Cl₂/isopropanol 95:5 (3×20 mL). The combined organicextract was washed with brine (10 mL), dried (Na₂SO₄) and evaporated.The residue was purified by flash-chromatography (eluant: ethylacetate-MeOH 5:1) yielding 390 (131 mg, 70%). Data for 390: MS (ESI) m/z985 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.25–8.05 (br s, 1H) 7.66(s, 1H), 5.12–4.90 (m, 3H).

Example 53 Synthesis of Triazoles 391–393

Scheme 75 depicts the synthesis of triazole 391. The oxime of2,4-dichlorobenzaldehyde was converted to hydroxyiminoyl chloride 464prior to cycloaddition to alcohol 465. Conversion of alcohol 465 toazide 466 and final cycloaddition to alkyne 173 afforded triazole 391.Triazoles 392 and 393 were synthesized in the same manner as compound391.

Synthesis of Oxime 463

To a suspension of 2,4-dichlorobenzenecarboxaldehyde (7.73 g, 44.2 mmol)in 100 mL 95% aqueous EtOH was added HCl.H₂NOH (3.69 g, 53.0 mmol)followed by a solution of NaOH (2.3 g, 57.4 mmol) in 4 mL of water at 0°C. The suspension was stirred at room temperature overnight, poured into300 mL ice/water and extracted with ethyl acetate (2×100 mL). Thecombined organic extract was washed with water (2×80 mL), brine (80 mL),dried (Na₂SO₄) and evaporated yielding 463 (8.2 g, 97%). Data for 463:¹HNMR (300 MHz, CDCl₃): δ 8.52 (s, 1H), 7.80–8.75 (m, 1H), 7.43–7.40 (m,1H), 7.29–7.20 (m, 1H).

Synthesis of Hydroxyiminoyl Chloride 464

To a solution of 463 (7.0 g, 36.8 mmol) in 30 mL DMF was added inportions N-chlorosuccinimide (5.4 g, 40.5 mmol) at 20–30° C. The mixturewas stirred at room temperature for 1 h, then poured into 200 mLice/water and extracted with ethyl acetate (2×100 mL). The combinedorganic extract was washed with water (3×80 mL), brine (80 mL), dried(Na₂SO₄) and evaporated yielding 464 (7.1 g, 86%). Data for 464: ¹HNMR(300 MHz, CDCl₃): δ 8.64 (s, 1H), 7.38–7.15 (m, 3H).

Synthesis of Alcohol 465

To a solution of allyl alcohol (1.33 mL, 19.6 mmol) in 58 mL CHCl₃ wasadded a 1M diethylzinc solution in hexanes (23.2 mL, 23.2 mmol) at −5 to0° C. After stirring for 10 min, (+)-diisopropyl tartrate (0.75 mL, 3.56mmol) was added and the solution was stirred for 1 h at 0° C. The milkysolution was cooled to −20° C. and 14 mL CHCl₃ and dioxane (1.97 mL,23.2 mmol) was added. Then 464 (4.00 g, 17.8 mmol) was added in portionsat −20 to −15° C. The solution was stirred for 4 h at −10° C., thenpoured into 200 mL 1M citric acid/ice and extracted with CHCl₃ (3×100mL). The combined organic extract was washed with brine (80 mL), dried(Na₂SO₄) and evaporated. The residue was purified byflash-chromatography (eluant: ethyl acetate-hexanes 2:3), yielding crude465, which was recrystallized from 1-chlorobutane, yielding pure 465(2.6 g, 60%). Data for 465: ¹HNMR (300 MHz, CDCl₃,): δ 7.76 (d, J=5 Hz,1H), 7.61 (s, 1H), 7.49–7.42 (m, 1H), 5.10–5.01 (m, 1H), 4.07 (dd, J=3,12 Hz, 1H), 4.03 (dd, J=3, 12 Hz, 1H), 3.73–3.52 (m, 2H), 2.18 (br s,1H).

Synthesis of Azide 466

To a solution of 465 (1.0 g, 4.1 mmol) in 20 mL dichloromethane wasadded Et₃N (1.0 mL, 7.3 mmol) followed by MsCl (0.37 mL, 4.9 mmol) at 0°C. The mixture was stirred at 0° C. for 1 h, poured into 50 mL water/iceand extracted with dichloromethane (2×40 mL). The combined organicextract was washed with water (2×20 mL), brine (20 mL), dried (Na₂SO₄)and evaporated. The residue was dissolved in 17 mL DMF, NaN₃ (0.53 g,8.1 mmol) was added, and the mixture was stirred at 80° C. for 2 h. Themixture was poured into 50 mL water/ice and extracted with ethyl acetate(2×50 mL). The combined organic extract was washed with water (3×20 mL),brine (20 mL), dried (Na₂SO₄) and evaporated. The residue was purifiedby flash-chromatography (eluant: hexanes-ethyl acetate 2:3) yielding 466(1.1 g, 98%). Data for 466: ¹HNMR (300 MHz, CDCl₃,): δ 7.65 (d, J=8 Hz,1H), 7.61 (d, J=1 Hz, 1H), 7.23–7.17 (m, 1H), 4.90–4.82 (m, 1H),3.61–3.21 (m, 4H).

Synthesis of Triazole 391

To a solution of alkyne 173 (150 mg, 0.191 mmol) in 6 mL acetonitrilewas added azide 466 (52 mg, 0.191 mmol), 2,6-lutidine (0.025 mL, 0.209mmol) and CuI (18.2 mg, 0.095 mmol). The mixture was stirred overnightat room temperature, poured into 10 mL 5% aqueous NH₃/ice and extractedwith CH₂Cl₂/isopropanol 95:5 (3×20 mL). The combined organic extract waswashed with brine (10 mL), dried (Na₂SO₄) and evaporated. The residuewas purified by flash-chromatography (eluant: ethyl acetate-MeOH 5:1)yielding 391 (157 mg, 78%). Data for 391: MS (ESI) m/z 1057 (M+H)⁺;¹HNMR (300 MHz, CDCl₃, partial): δ 8.30–8.10 (br s, 1H), 7.52 (s, 1H),7.39–7.20 (m, 3H), 5.15–5–02 (m, 1H).

Synthesis of Triazole 392

To a suspension of 4-chloro-3-fluorobenzaldehyde (5.00 g, 31.5 mmol) in90 mL 95% aqueous EtOH was added HCl.H₂NOH (2.63 g, 37.8 mmol) followedby a solution of NaOH (1.90 g, 47.3 mmol) in 3 mL of water at 0° C. Thesuspension was stirred at room temperature for 3 h, then poured into 200mL ice/water and extracted with ethyl acetate (2×100 mL). The combinedorganic extract was washed with water (2×80 mL), brine (80 mL), dried(Na₂SO₄) and evaporated. The residue was dissolved in 25 mL DMF andN-chlorosuccinimide (4.23 g, 34.7 mmol) was added in portions at 30–40°C. The mixture was stirred at room temperature for 1 h, then poured into200 mL ice/water and extracted with ethyl acetate (2×100 mL). Thecombined organic extract was washed with water (3×80 mL), brine (80 mL),dried (Na₂SO₄) and evaporated yielding the hydroxyiminoyl chloride (3.71g., 62%). Data: ¹HNMR (300 MHz, CDCl₃): δ 8.15 (s, 1H), 7.60–7.51 (m,2H), 7.41–7.32 (m, 1H).

To a solution of allyl alcohol (1.16 mL, 17.0 mmol) in 50 mL CHCl₃ at −5to 0° C. was added a 1M diethylzinc solution in hexanes (20.1 mL, 20.1mmol). After stirring for 10 min, (+)-diisopropyl tartrate (0.65 mL,3.09 mmol) was added and the solution was stirred for 1 h at 0° C. Themilky solution was cooled to −20° C. and 12 mL CHCl₃ and dioxane (1.70mL, 20.1 mmol) was added. Then the above hydroxyiminoyl chloride (3.21g, 15.4 mmol) was added in portions at −20 to −15° C. The solution wasstirred for 3 h at −15° C., then poured into 200 mL 1M citric acid/iceand extracted with CHCl₃ (3×100 mL). The combined organic extract waswashed with brine (80 mL), dried (Na₂SO₄) and evaporated. The residuewas purified by flash-chromatography (eluant: ethyl acetate-hexanes 1:2and 1:2), yielding crude material which was recrystallized twice from1-chlorobutane, yielding the expected isoxazoline alcohol (1.5 g, 42%).Data: ¹HNMR (300 MHz, CDCl₃,): δ 7.48–7.21 (m, 3H), 4.82–4–74 (m, 1H),3.82–3.76 (m, 1H), 3.58–3.53 (m, 1H), 3.27–3.09 (m, 2H).

To a solution of the above alcohol (1.0 g, 4.4 mmol) in 20 mLdichloromethane was added Et₃N (1.1 mL, 7.8 mmol) followed by MsCl (0.41mL, 5.2 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h, thenpoured into 50 mL water/ice and extracted with dichloromethane (2×40mL). The combined organic extract was washed with water (2×20 mL), brine(20 mL), dried (Na₂SO₄) and evaporated. The residue was dissolved in 15mL DMF, NaN₃ (0.57 g, 8.7 mmol) was added and the mixture was stirred at80° C. for 2 h. The mixture was poured into 50 mL water/ice andextracted with ethyl acetate (2×50 mL). The combined organic extract waswashed with water (3×20 mL), brine (20 mL), dried (Na₂SO₄) andevaporated. The residue was purified by flash-chromatography (eluant:hexanes-ethyl acetate 2:3) yielding the expected azide (1.1 g, 95%).Data: ¹HNMR (300 MHz, CDCl₃,): δ 7.43–7.29 (m, 3H), 4.93–4.84 (m, 1H),3.54–3.27 (m, 3H), 3.18–3.30 (m, 1H).

To a solution of alkyne 173 (150 mg, 0.191 mmol) in 6 mL acetonitrilewas added the above azide (49.5 mg, 0.191 mmol), 2,6-lutidine (0.0245mL, 0.209 mmol) and CuI (18.2 mg, 0.095 mmol). The mixture was stirredovernight at room temperature, poured into 10 mL 5% aqueous NH₃/ice andextracted with CH₂Cl₂/isopropanol 95:5 (3×20 mL). The combined organicextract was washed with brine (10 mL), dried (Na₂SO₄) and evaporated.The residue was purified by flash-chromatography (eluant: ethylacetate-MeOH 5:1) yielding 392 (138 mg, 70%). Data for 392: MS (ESI) m/z1042 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.45–8.32 (br s, 1H),7.28–7.19 (m, 2H), 7.13–7.10 (m, 1H), 5.05–4.82 (m, 2H).

Synthesis of Triazole 393

To a solution of alkyne 173 (150 mg, 0.191 mmol) in 6 mL acetonitrilewas added azide 342 (45.4 mg, 0.191 mmol), 2,6-lutidine (0.025 mL, 0.209mmol) and CuI (18.2 mg, 0.095 mmol). The mixture was stirred overnightat room temperature, then poured into 10 mL 5% aqueous NH₃/ice andextracted with CH₂Cl₂/isopropanol 95:5 (3×20 mL). The combined organicextract was washed with brine (10 mL), dried (Na₂SO₄) and evaporated.The residue was purified by flash-chromatography (eluant: ethylacetate-MeOH 5:1) yielding 393 (118 mg, 60%). Data for 393: MS (ESI) m/z1025 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.00 (br s, 1H), 7.52(m, 3H), 5.11–4.95 (m, 1H), 4.95–4.82 (m, 2H).

Example 54 Synthesis of Triazoles 394–403

Scheme 76 depicts the synthesis of azides 469, 482–487, 489, 491, and495 required for the synthesis of triazoles 394–403. The azides werethen treated with alkyne 173 to afford the final targets.

Synthesis of Hydroxyiminoyl Chloride 467

To a solution of 3-formyl-6-fluoropyridine (1.77 g, 9.36 mmol) in EtOH(10 mL) at 0° C. was added water (5 mL), then hydroxylamine (1.00 g,14.0 mmol), followed by the addition of NaOH (2.20 mL, 50% w/w). Themixture was stirred at 0° C. for 15 min. The EtOH was evaporated, thenEtOAc (50 mL) was added. HCl (1 M) was used to the adjust pH to 6. Theaqueous phase was extracted with EtOAc (30 mL×2), and the organicextracts were dried by Na₂SO₄. The concentrated residue (1.50 g) wasused in the next step without further purification.

To a solution of the crude intermediate above (1.50 g, in DMF (20 mL) atroom temperature was added N-chlorosuccinimide (1.80 g, 13.1 mmol) intwo portions. The mixture was stirred at 45–50° C. for 1 h, then brine(50 mL) and saturated aqueous Na₂CO₃ (3 mL) was added. The mixture wasextracted with EtOAc/Hexane (200 mL, 1/1). The organic layer was washedby brine (200 mL), dried by MgSO₄, to give hydroximinoyl chloride 467(1.45 g, 60% yield). Data for 467: ¹HNMR (300 MHz, CDCl₃): δ 8.72 (d,J=3 Hz, 1H), 8.45 (s, 1H), 8.30–8.20 (m, 1H), 7.00 (dd, J=9, 3 Hz, 1H).

Synthesis of Hydroxyiminoyl Chlorides 470–475

These hydroxyiminoyl chlorides were synthesized from the appropriatearyl aldehyde using the above procedure for the synthesis of 467.

Data for 470: ¹HNMR (300 MHz, CDCl₃): δ 9.27 (s, 1H), 8.86 (d, J=3 Hz,1H), 7.90–7.70 (m, 1H), 7.54 (d, J=8 Hz, 1H).

Data for 471: ¹HNMR (300 MHz, CDCl₃): δ 8.16 (s, 1H), 7.94 (d, J=8 Hz,2H), 7.67 (d, J=8 Hz, 2H).

Data for 472: ¹HNMR (300 MHz, CDCl₃): δ 8.53 (s, 1H), 8.02 (d, J=8 Hz,1H), 7.70 (d, J=8 Hz, 1H), 7.56 (d, J=8 Hz, 1H).

Data for 475: ¹HNMR (300 MHz, CDCl₃): δ 8.08 (s, 1H), 7.58–7.22 (m, 1H).

Synthesis of Alcohol 468

To a solution of allyl alcohol (661 μL, 9.62 mmol) in CHCl₃ (30 mL) at0° C. was added diethylzinc (12.03 mL, 12.03 mmol). After the mixturewas stirred at 0° C. for 15 min, (+)-diisopropyl tartrate (855 μL, 4.01mmol) in CHCl₃ (5.0 mL) was added. The mixture was stirred at 0° C. for1 h, then hydroximinoyl chloride 467 (1.40 g, 8.02 mmol) in CHCl₃ (10.0mL) was added dropwise over 10 min. The mixture was stirred at 0° C. for2 h, then sat. aqueous NH₄Cl (20 mL) and citric acid (6 mL, 1 M) wasadded. The mixture was extracted with CH₂Cl₂ (50 mL×4), and the organicextracts were dried by Na₂SO₄. The residue was puriifed byflash-chromatography (eluant: 2.5/100 MeOH/CH₂Cl₂), to provide 468 (1.40g, 89% yield; >95% ee). Data for 468: ¹HNMR (300 MHz, CDCl₃): δ 8.39 (d,J=3 Hz, 1H), 8.25–8.15 (m, 1H), 7.00 (dd, J=9, 3 Hz, 1H), 4.98–4.88 (m,1H), 3.94 (dd, J=12, 3 Hz, 1H), 3.72 (dd, J=12, 4 Hz, 1H), 3.69–3.25 (m,2H).

Synthesis of Alcohols 476–481

These alcohols were synthesized from the appropriate hydroxyiminoylchlorides using the above procedure for the synthesis of 468.

Data for 476: ¹HNMR (300 MHz, CDCl₃): δ 8.54 (d, J=3 Hz, 1H), 7.92 (dd,J=11, 3 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 4.99–4.90 (m, 1H), 3.94 (dd,J=12, 3 Hz, 1H), 3.71 (dd, J=12, 4 Hz, 1H), 3.47–3.93 (m, 2H).

Data for 477: ¹HNMR (300 MHz, CDCl₃): δ 7.77 (d, J=8 Hz, 2H), 7.65 (d,J=8 Hz, 2H), 4.93 (dddd, J=13, 8, 4, 3 Hz, 1H), 3.93 (dd, J=13, 3 Hz,1H), 3.70 (dd, J=13, 4 Hz, 1H), 3.40 (dd, J=17, 11 Hz, 1H), 3.32 (dd,J=17, 8 Hz, 1H).

Data for 478: ¹HNMR (300 MHz, CDCl₃): δ 7.87 (d, J=8 Hz, 1H), 7.84 (d,J=8 Hz, 1H), 7.65 (d, J=8 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 4.93 (dddd,J=13, 8, 3, 3 Hz, 1H), 3.92 (dd, J=13, 3 Hz, 1H), 3.70 (dd, J=13, 4 Hz,1H), 3.43 (dd, J=11, 7 Hz, 1H), 3.33 (dd, J=11, 8 Hz, 1H).

Data for 479: ¹HNMR (300 MHz, CDCl₃): δ 7.76 (d, J=7 Hz, 2H), 7.31 (d,J=7 Hz, 2H), 4.96 (dddd, J=13, 8, 4, 3 Hz, 1H), 3.96 (dd, J=12, 3 Hz,1H), 3.75 (dd, J=12, 5 Hz), 3.44 (dd, J=17, 10 Hz, 1H), 3.34 (dd, J=17,8 Hz, 1H).

Data for 480: ¹HNMR (300 MHz, CDCl₃): δ 7.58 (d, J=8 Hz, 1H), 7.54 (s,1H), 7.44 (d, J=8 Hz, 1H), 7.31–7.24 (m, 1H), 4.92 (dddd, J=12, 8, 4, 3Hz, 1H), 3.94 (dd, J=5, 3 Hz, 1H), 3.90 (dd, J=5, 3 Hz, 1H), 3.72 (dd,J=8, 4 Hz, 1H), 3.68 (dd, J=8, 4 Hz, 1H).

Data for 481: ¹HNMR (300 MHz, CDCl₃): δ 7.27 (s, 1H), 7.20 (s, 1H), 4.83(dddd, J=12, 8, 3, 3 Hz, 1H), 3.87 (dd, J=12, 3 Hz, 1H), 3.67 (dd, J=12,4 Hz, 1H), 3.37–3.17 (m, 2H).

Synthesis of Azide 469

To a solution of alcohol 468 (700 mg, 3.57 mmol) in CH₂Cl₂ (20 mL) at 0°C. was added Et₃N, followed by the addition of MsCl (416 μL, 5.35 mmol).The mixture was stirred at 0° C. for 30 min, then EtOAc (100 mL) wasadded, and the mizture was washed with brine (100 mL×2), dried withMgSO₄, and evaporated to afford the crude mesylate (800 mg).

A mixture of the above mesylate (800 mg, 3.57 mmol) and NaN₃ in DMF (15mL) was stirred at 80° C. for 3 h, then the mixture was poured intowater (50 mL), extracted with Et₂O (30 mL×3), dried with Na₂SO₄, andevaporated to afford azide 469 (540 mg, 68% yield). Data for 469: ¹HNMR(300 MHz, CDCl₃): δ 8.39 (s, 1H), 8.30–8.20 (m, 1H), 7.03 (dd, J=8, 3Hz, 1H), 4.40–4.30 (m, 1H), 3.60 (dd, J=10, 5 Hz, 1H), 3.55–3.35 (m,2H), 3.25 (dd, J=16, 7 Hz, 1H).

Synthesis of Azides 482–487

These azides were synthesized from the appropriate alcohols using theabove procedure for the synthesis of 469.

Data for 482: ¹HNMR (300 MHz, CDCl₃): δ 8.46 (d, J=3 Hz, 1H), 7.88 (dd,J=9, 2 Hz, 1H), 7.49 (dd, J=9, 2 Hz, 1H), 5.00–4.80 (m, 1H), 3.53 (dd,J=10, 4 Hz, 1H), 3.53–3.30 (m, 2H), 3.16 (dd, J=17, 7 Hz, 1H).

Data for 483: ¹HNMR (300 MHz, CDCl₃): δ 7.79 (d, J=8 Hz, 2H), 7.68 (d,J=8 Hz, 2H), 5.13–5.02 (m, 1H), 4.43 (dd, J=11, 4 Hz, 1H), 4.37 (dd,J=11, 5 Hz, 1H), 3.53 (dd, J=17, 11 Hz, 1H), 3.33 (dd, J=9, 7 Hz, 1H).

Data for 484: ¹HNMR (300 MHz, CDCl₃): δ 7.87 (dd, J=9, 9 Hz, 1H), 7.70(d, J=8 Hz, 1H), 7.56 (dd, J=8, 8 Hz, 1H), 5.13–5.02 (m, 1H), 4.46–4.30(m, 2H), 3.53 (dd, J=17, 11 Hz, 1H), 3.36 (dd, J=9, 7 Hz, 1H).

Data for 485: ¹HNMR (300 MHz, CDCl₃): δ 7.65 (d, J=9 Hz, 2H), 7.19 (d,J=8 Hz, 2H), 4.93–4.85 (m, 1H), 3.50 (dd, J=13, 5 Hz, 1H), 3.43–3.30 (m,2H), 3.15 (dd, J=13, 7 Hz, 1H).

Data for 486: ¹HNMR (300 MHz, CDCl₃): δ 7.67–750 (m, 4H), 4.94–4.84 (m,1H), 3.50 (dd, J=13, 5 Hz, 1H), 3.45–3.25 (m, 2H), 3.20 (dd, J=13, 7 Hz,1H).

Data for 487: ¹HNMR (300 MHz, CDCl₃): δ 7.67–750 (m, 4H), 4.94–4.84 (m,1H), 3.50 (dd, J=13, 5 Hz, 1H), 3.45–3.25 (m, 2H), 3.20 (dd, J=13, 7 Hz,1H).

Synthesis of Alcohol 488

A mixture of alcohol 348 (310 mg, 1.21 mmol),3-(tributyl)stannylpyridine (446 mg, 1.21 mmol), Pd(dppf)₂Cl₂ (59 mg,0.072 mmol), copper (I) chloride (12 mg), lithium chloride (305 mg, 7.20mmol) in DMSO (3.0 mL) was degassed by argon and then was stirred at 60°C. for 16 h. The reaction was quenched by the addition of H₂O (50 mL),NH₄OH (0.2 mL), EtOAc (150 mL) and CH₂Cl₂ (20 mL). The mixture waspassed through celite. The organic layer was washed with water (50mL×3), dried with Na₂SO₄, and the residue was purified byflash-chromatography (eluant: MeOH/CH₂Cl₂, 2/100), to give 488 (265 mg).Data for 488: ¹HNMR (300 MHz, CDCl₃): δ 8.88 (s, 1H), 8.63 (d, J=4 Hz,1H), 7.92 (d, J=8 Hz, 1H), 7.89 (d, J=8 Hz, 2H), 7.64 (d, J=8 Hz, 1H),7.41 (dd, J=8, 5 Hz, 1H), 4.92 (dddd, J=12, 8, 3, 3 Hz, 1H), 3.92 (dd,J=12, 3 Hz, 1H), 3.72 (dd, J=12, 5 Hz, 1H), 3.44 (dd, J=17, 11 Hz, 1H),3.33 (dd, J=17, 8 Hz, 1H).

Synthesis of Azide 489

The azide was synthesized using the same procedure as described abovefor the synthesis of azide 469. Data for 489: ¹HNMR (300 MHz, CDCl₃): δ8.85 (s, 1H), 8.60 (m, 1H), 7.85 (d, J=8 Hz, 1H), 7.73 (d, J=9 Hz, 2H),7.58 (d, J=9 Hz, 2H), 7.36 (s, 1H), 4.96–4.84 (m, 1H), 3.54 (dd, J=13, 5Hz, 1H), 3.45–3.35 (m, 2H), 3.20 (dd, J=13, 7 Hz, 1H).

Synthesis of Alcohol 490

This compound was synthesized from alcohol 476 using the proceduredescribed above for the synthesis of 488. Data for 490: ¹HNMR (300 MHz,CDCl₃): δ 9.17 (s, 1H), 8.86 (d, J=2 Hz, 1H), 8.62 (s, 1H), 8.30 (d, J=8Hz, 1H), 8.08 (dd, J=8, 2 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.37 (dd, J=8,5 Hz, 1H), 4.93–4.84 (m 1H), 3.88 (d, J=10 Hz, 1H), 3.66 (d, J=10 Hz,1H), 3.44–3.20 (m, 2H).

Synthesis of Azide 491

This azide was synthesized from alcohol 490 using the same proceduredescribed above for the synthesis of azide 469. Data for 491: ¹HNMR (300MHz, CDCl₃): δ 8.82 (s, 1H), 8.30–8.20 (m, 2H), 8.28–8.18 (m, 2H), 7.76(d, J=9 Hz, 1H), 7.40 (s, 1H), 4.96–4.86 (m, 1H), 3.59–3.20 (m, 4H),3.20 (dd, J=13, 7 Hz, 1H).

Synthesis of Silylether 493

To a solution of alcohol 460 (360 mg, 2.00 mmol) in DMF (8.0 mL) at 0°C. was added t-butyldimethylsilyl chloride (461 mg, 3.00 mmol), followedby the addition of imidazole (275 mg, 4.0 mmol). The mixture was stirredat 0° C. for 1 h and room temperature for 16 h. Water (50 mL) was added,and the mixture was extracted with 30% EtOAc in hexane (50 mL×3). Theorganic phase was washed with water (50 mL×2), dried by Na₂SO₄, andevaporated. The residue was purified by flash-chromatography (eluant:EtOAc/hexane, 5/95), to afford 493 (580 mg, 98% yield). Data for 493:¹HNMR (300 MHz, CDCl₃, ppm): δ 4.70–4.61 (m, 1H), 3.69 (dd, J=11, 4 Hz,1H), 3.62 (dd, J=11, 4 Hz, 1H), 0.81 (s, 9H), 0.01 (s, 6H).

Synthesis of Azide 495

Alcohol 348 (1.00 g, 3.90 mmol) and PdCl₂(dppf)₂ (546 mg, 0.762 mmol)were dissolved in dioxane (11 mL) and hexamethylditin (1.42 g, 4.30mmol) was added. The mixture was stirred at 85° C. for 16 h, then sat.aqueous NaHCO₃ (20 mL) was added, followed by EtOAc (20 mL). The aqueousphase was extracted with EtOAc (40 mL×3), and the organic phase wasdried by Na₂SO₄. The residue was purified by flash-chromatography(eluant: EtOAc/hexane, 35/65) to afford stannane 492 (740 mg, 56%yield). Data for 492: ¹HNMR (300 MHz, CDCl₃): δ 7.13 (d, J=6 Hz, 2H),7.05 (d, J=6 Hz, 2H), 4.70–4.60 (m, 1H), 3.70–3.61 (m, 3H), 3.51–3.41(m, 1H), 3.17 (dd, J=17, 11 Hz, 1H), 3.05 (dd, J=17, 8 Hz, 1H), 1.73(dd, J=8, 6 Hz, 1H), 0.09 (s, 9H).

To a suspension of stannane 492 (340 mg, 1.00 mmol), bromide 493 (353mg, 1.20 mmol) and lithium chloride (254 mg, 6.00 mmol) in DMSO (2.5 mL)was added PdCl₂(dppf)₂ (49 mg, 0.06 mmol). The mixture was stirred at70° C. for 16 h, then water (50 mL) was added. The mixture was extractedwith EtOAc (40 mL×3), and the extracts were dried by Na₂SO₄. The residuewas purified by flash-chromatography (eluant: EtOAc/hexane, 35/65) toafford alcohol 494 (21 mg, 63% yield). Data for 494: ¹HNMR (300 MHz,CDCl₃): δ 7.56 (d, J=8 Hz, 2H), 7.22 (d, J=8 Hz, 2H), 4.90–4.81 (m, 1H),3.87 (dd, J=16, 3 Hz, 3H), 3.68 (dd, J=16, 5 Hz, 1H), 3.38 (dd, J=17, 8Hz, 1H), 3.25 (dd, J=17, 8 Hz, 1H), 2.38 (s, 3H).

Azide 495 was synthesized from alcohol 494 using the same proceduredescribed above for the synthesis of azide 469. Data for 495: ¹HNMR (300MHz, CDCl₃): δ 7.50 (d, J=8 Hz, 2H), 7.15 (d, J=8 Hz, 2H), 4.86–4.76 (m,1H), 3.45–3.30 (m, 3H), 3.13 (dd, J=17, 7 Hz, 1H).

General Procedure for the Synthesis of Triazoles 394–403

To a mixture of alkyne 173 (100 mg, 0.127 mmol) and the appropriateazide (0.140 mmol, 1.1 eq) in acetonitrile (4.0 mL) at room temperatureunder argon was added 2,6-lutidine (22 μL, 0.191 mmol, 1.1 eq), followedby addition of copper (I) iodide (12 mg, 0.064 mmol). The mixture wasstirred at room temperature for 1.5 to 6 h. After the reaction wascomplete, 1 mL 5% NH₄OH was added. The mixture was stirred at roomtemperature for 10 min. The reaction solvent (CH₃CN) was removed undervacuum. The aqueous phase was extracted with CH₂Cl₂ (30 mL×3), and theorganic phase was dried over Na₂SO₄. The residue was separated byflash-chromatography (eluant: 20/80 to 30/70 MeOH/EtOAc) on silica gelto afford the desired product.

Data for 394: MS (ESI) m/z 1008.4 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 8.37 (s, 1H), 8.37–8.00 (m, 1H), 7.60 (s, 1H), 7.00 (dd, J=9, 3 Hz,1H), 4.45 (d, J=6 Hz, 1H), 4.29 (br s, 1H), 2.24 (s, 3H), 1.04 (d, J=9Hz, 3H).

Data for 395: MS (ESI) m/z 1070.2 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 8.45 (s, 1H), 7.73 (dd, J=4, 2 Hz, 1H), 7.47 (d, J=4 Hz, 1H), 4.45 (d,J=6 Hz, 1H), 4.29 (br s, 1H), 2.20 (s, 3H), 0.98 (d, J=9 Hz, 3H).

Data for 396: MS (ESI) m/z 1043.7 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 7.48 (s, 1H), 7.16 (d, J=7 Hz, 2H), 7.14 (d, J=7 Hz, 2H), 4.36 (d, J=7Hz, 1H), 4.22 (s, 1H), 2.21 (s, 3H), 0.96 (d, J=8 Hz, 3H).

Data for 397: MS (ESI) m/z 1073.8 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 7.64 (d, J=8 Hz, 2H), 7.24 (d, J=8 Hz, 2H), 4.40 (d, J=9 Hz, 1H), 4.28(s, 1H), 2.27 (s, 3H), 1.04 (d, J=9 Hz, 3H).

Data for 398: MS (ESI) m/z 1073.8 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 7.53 (s, 1H), 7.43–7.34 (m, 3H), 7.22 (s, 1H), 4.36 (d, J=7 Hz, 1H),4.21 (s, 1H), 2.20 (s, 3H), 0.96 (d, J=8 Hz, 3H).

Data for 399: MS (ESI) m/z 1057.8 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 7.64 (d, J=8 Hz, 2H), 7.58 (d, J=8 Hz, 1H), 7.51 (br s, 1H), 4.55 (t,J=5 Hz, 2H), 4.36 (d, J=10 Hz, 1H), 4.21 (s, 1H), 2.25 (s, 3H), 0.95 (d,J=8 Hz, 3H).

Data for 400: MS (ESI) m/z 1057.8 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 7.78 (s, 1H), 7.70 (d, J=8 Hz, 1H), 7.60 (d, J=8 Hz, 1H), 7.53–7.44(m, 2H), 4.46 (d, J=7 Hz, 1H), 4.21 (s, 1H), 2.20 (s, 3H), 0.96 (d, J=8Hz, 3H).

Data for 401: MS (ESI) m/z 1003.8 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 7.60 (s, 1H), 7.48 (d, J=8 Hz, 2H), 7.19 (d, J=8 Hz, 2H), 4.43 (d, J=7Hz, 1H), 4.22 (s, 1H), 2.27 (s, 3H), 1.04 (d, J=8 Hz, 3H).

Data for 402: MS (ESI) m/z 1066.9 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 8.79 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.82 (dt, J=8, 2 Hz, 1H), 7.65 (d,J=8 Hz, 2H), 7.56 (d, J=8 Hz, 2H), 7.53 (s, 1H), 7.33 (dd, J=8, 4 Hz,1H), 4.37 (d, J=7 Hz, 1H), 4.21 (s, 1H), 2.20 (s, 3H), 0.97 (d, J=8 Hz,3H).

Data for 403: MS (ESI) m/z 1067.8 (M)⁺; ¹HNMR (300 MHz, CDCl₃, partial):δ 9.16 (s, 1H), 8.62 (d, J=4 Hz, 1H), 7.82 (dt, J=8, 2 Hz, 1H), 7.96(dd, J=6, 2 Hz, 1H), 7.74 (d, J=8 Hz, 1H), 7.51 (s, 1H), 7.37 (dd, J=8,5 Hz, 1H), 4.36 (d, J=7 Hz, 1H), 4.21 (s, 1H), 2.20 (s, 3H), 0.96 (d,J=8 Hz, 3H).

Example 55 Synthesis of Triazoles 404 and 405

Synthesis of Azide 404

This compound (189 mg) was synthesized from alkyne 174 (150 mg, 0.187mmol) and azide 349 (58 mg, 0.206 mmol) using the same proceduredescribed above for the synthesis of triazole 361. Data for 404: MS(ESI) m/z 542 (M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃, partial): δ 7.53–7.50(m, 3H), 7.45–7.42 (m, 2H), 5.17–5.11 (m, 1H), 5.08 (d, J=4 Hz, 1H),4.69–4.66 (m, 1H), 4.61 (t, J=5 Hz, 2H), 4.45 (d, J=7 Hz, 1H), 3.33 (s,3H), 3.03 (t, J=9 Hz, 1H), 2.21 (t, J=5 Hz, 4H), 0.89 (m, 6H).

Synthesis of Azide 405

This compound (175 mg) was made from alkyne 174 (150 mg, 0.187 mmol) andazide 503 (49 mg, 0.206 mmol; see Example 58 for the synthesis of 503)using the same procedure described above for the synthesis of triazole361. Data for 405: MS (ESI) m/z 520.5 (M+2H)²⁺; ¹H NMR (300 MHz, CDCl₃,partial): δ 7.49 (s, 1H), 7.12–7.05 (m, 2H), 6.91–6.82 (m, 1H),5.21–5.13 (m, 1H), 5.12 (d, J=5 Hz, 1H), 4.61 (t, J=4 Hz, 2H), 4.44 (d,J=7 Hz, 1H), 4.29 (br d, J=3 Hz, 1H), 4.13–4.03 (m, 1H), 3.69 (d, J=6Hz, 1H), 3.65 (d, J=7 Hz, 1H), 3.03 (t, J=10 Hz, 1H), 0.91–0.87 (m, 6H).

Example 56 Synthesis of Triazoles 406–409

These triazoles were synthesized using the procedure described above forthe synthesis of triazole 228.

Synthesis of Triazole 406

Alkyne 174 (70 mg, 86 μmol), azide 355 (39 mg, 129 μmol), and CuI (2 mg,8 μmol) afforded triazole 406 as a white solid (94.1 mg, 83 μmol). Datafor 406: MS (ESI) m/z 568 (M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ9.46 (br s, 1H), 7.69–7.53 (m, 8H), 7.44 (s, 1H), 5.20–5.04 (m, 3H),4.70–4.58 (m, 2H), 4.41 (d, J=6 Hz, 1H), 4.20 (br s, 1H), 4.12–4.00 (m,1H), 3.61 (d, J=3 Hz, 1H), 3.56 (d, J=7 Hz, 1H), 3.33 (s, 3H), 3.05–2.93(m, 2H), 2.29 (s, 3H), 2.18 (s, 3H), 2.10 (d, J=9 Hz, 1H), 1.34–1.14 (m,17H), 0.91–0.84 (m, 6H): ¹³CNMR (75 MHz, CDCl₃): δ 178.9, 156.3, 148.4,144.4, 141.0, 132.7, 128.9, 127.6, 127.5, 127.4, 122.3, 118.6, 111.6,102.9, 94.5, 83.3, 79.2, 78.2, 77.7, 74.2, 73.7, 73.0, 70.6, 70.1, 68.8,65.9, 65.5, 62.4, 53.1, 52.4, 49.5, 45.3, 42.3, 37.4, 36.8, 36.2, 34.7,29.6, 27.8, 27.6, 26.9, 26.8, 25.4, 22.0, 21.6, 21.3, 21.2, 18.2, 16.2,14.5, 11.2, 8.8, 7.9.

Synthesis of Triazole 407

Alkyne 174 (70 mg, 86 μmol), azide 349 (36 mg, 129 μmol), and CuI (2 mg,8 μmol) afforded triazole 407 as a white solid (89 mg, 80 μmol). Datafor 407: MS (ESI) m/z 556, 557 (M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃,partial): δ 9.38 (br s, 1H), 7.54–7.41 (m, 5H), 7.44 (s, 1H), 5.20–4.90(m, 3H), 4.70–4.58 (m, 3H), 4.49 (d, J=6 Hz, 1H), 4.28 (br s, 1H),4.12–4.00 (m, 1H), 3.61 (d, J=3 Hz, 1H), 3.32 (s, 3H), 3.05–2.93 (m,2H), 2.30 (s, 3H), 2.17 (s, 3H), 2.15 (d, J=9 Hz, 1H), 1.33–1.27 (m,6H), 1.27–1.15 (m, 10H), 1.10–1.00 (m, 8H), 0.91–0.84 (m, 6H), ¹³CNMR(75 MHz, CDCl₃): δ 178.8, 156.0, 148.4, 132.0, 128.1, 127.6, 124.8,122.3, 102.9, 94.5, 83.3, 79.2, 78.2, 77.7, 74.3, 73.7, 73.0, 70.6,70.1, 68.8, 65.9, 65.5, 62.4, 53.4, 53.1, 52.4, 49.5, 45.3, 42.2, 37.2,36.8, 36.2, 34.7, 29.6, 27.8, 27.6, 26.9, 26.8, 25.4, 22.0, 21.6, 21.4,21.3, 18.2, 16.2, 14.6, 11.2, 8.9, 7.4.

Synthesis of Triazole 408

Alkyne 174 (70 mg, 86 μmol), azide 158 (39 mg, 129 μmol), and CuI (2 mg,8 μmol) afforded triazole 408 as a white solid (93 mg, 85 μmol). Datafor 408: MS (ESI) m/z 560 (M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ7.70 (br s, 1H), 7.50 (s, 1H), 7.31 (dd, J=14, 2 Hz, 1H), 7.21 (dd, J=8,2 Hz, 1H), 6.89 (t, J=9 Hz, 3H), 5.14–5.05 (m, 1H), 4.97 (d, J=4 Hz,1H), 4.65–4.45 (m, 3H), 4.45 (d, J=7 Hz, 1H), 4.28 (dd, J=6, 2 Hz, 1H),4.13–3.97 (m, 1H), 3.87–3.80 (m, 4H), 3.68–3.61 (m, 3H), 3.32 (s, 3H),2.28 (s, 3H), 2.18 (d, J=9 Hz, 1H), 2.13 (s, 3H), 1.35–1.15 (m, 18H),1.10–1.02 (m, 9H), 0.91–0.82 (m, 6H): ¹³CNMR (75 MHz, CDCl₃): δ 178.3,153.3, 148.3, 133.4, 122.5, 122.3, 118.2, 114.5, 114.2, 103.0, 95.4,84.0, 79.0, 78.1, 77.6, 77.5, 77.1, 76.6, 73.5, 72.8, 70.7, 70.0, 68.7,66.7, 65.6, 65.5, 61.8, 53.1, 52.4, 50.4, 50.3, 49.4, 44.9, 42.5, 40.9,37.4, 36.8, 36.6, 35.0, 29.7, 27.8, 27.3, 26.9, 26.7, 25.4, 21.9, 21.6,21.4, 18.4, 16.3, 15.5, 11.2, 8.9, 7.4.

Synthesis of Triazole 409

Alkyne 174 (70 mg, 86 μmol), the azide 503 (31 mg, 129 μmol; see Example58 for the synthesis of 503), and CuI (2 mg, 8 μmol) afforded triazole409 as a white solid (93 mg, 85 μmol). Data for 409: MS (ESI) m/z 527(M+2H)²⁺; ¹HNMR (300 MHz, CDCl₃, partial): δ 8.95 (br s, 1H), 7.47 (s,1H), 7.12–7.03 (m, 2H), 6.71 (tt, J=9, 2 Hz, 1H), 5.21–5.09 (m, 2H),4.62 (d, J=6 Hz, 1H), 4.48 (t, J=10 Hz, 1H), 4.45 (d, J=7 Hz, 1H), 4.29(br s, 1H), 4.15–4.00 (m, 1H), 3.66 (d, J=5 Hz, 1H), 3.62 (d, J=7 Hz,1H), 3.32 (s, 3H), 3.02 (t, J=11 Hz, 1H), 2.29 (s, 3H), 2.18 (d, J=10Hz, 1H), 2.13 (s, 3H), 1.77 (d, J=9 Hz, 1H), 1.33–1.26 (m, 6H),1.27–1.15 (m, 10H), 1.10–0.99 (m, 9H), 0.92–0.84 (m, 6H): ¹³CNMR (75MHz, CDCl₃, partial): δ 178.7, 155.2, 148.4, 131.6, 122.2, 109.9, 109.8,109.6, 109.5, 105.7, 02.9, 94.6, 83.4, 79.6, 78.1, 77.9, 76.6, 74.3,73.9, 73.6, 72.9, 70.6, 70.1, 68.8, 65.8, 65.5, 62.3, 53.1, 52.3, 49.4,45.2, 42.4, 42.0, 37.0, 36.8, 36.3, 34.8, 29.6, 27.8, 27.5, 27.0, 26.7,25.4, 21.9, 21.6, 21.6, 21.3, 21.2, 18.2, 16.2, 11.2, 7.5.

Example 57 Synthesis of Triazoles 410 and 411

These triazoles were synthesized using the chemistry illustrated fortriazole 410 shown in Scheme 77. Racemic azide 499 was used to generatetriazole 410 as a mixture of diastereomers.

Synthesis of Azide 499

A solution of 3-fluoro-4-methoxybenzaldehyde (2.0 g, 12.97 mmol) andhydroxylamine hydrochloride (1.0 g, 14.27 mmol) in ethanol (40 mL) andwater (80 mL) was cooled to 4° C., and 2.3 mL NaOH (50% w/w) was added.The reaction mixture was stirred for 3 h at room temperature. Thereaction mixture was adjusted to pH 6.0, and partitioned with methylenechloride and water. The aqueous layer was extracted twice with methylenechloride, and the combined organic layer was washed with brine, dried(Na₂SO₄), and evaporated to yield 496 (1.97 g, 90%) as a white solid.Data for 496: ¹HNMR (300 MHz, CDCl₃): v 7.84 (s, 1H), 7.04 (d, J=3 Hz,1H), 6.74 (app t, J=8 Hz, 1H).

To a solution of oxime 496 (1.97 g, 11.64 mmol) in dimethylformamide (10mL) was added N-chlorosuccinimide (1.5 g, 11.64 mmol). The reactionmixture was warmed to 50° C. for 1 h. The reaction was diluted withethyl acetate (50 mL), and washed with brine. The organic phase wasdried (Na₂SO₄), and evaporated to yield 497 (2.37 g, 100% yield). Datafor 497: ¹HNMR (300 MHz, CDCl₃): δ 8.02 (s, 1H), 7.60 (m, 1H), 6.94 (t,J=3 Hz, 1H).

To a solution of hydroximinoyl chloride 497 (1.00 g, 4.91 mmol) inmethylene chloride (5 mL) was added allyl alcohol (0.3 mL, 4.91 mmol).The mixture was cooled to 0° C., and triethylamine (0.68 mL, 4.91 mmol)was added. The reaction mixture was slowly warmed to room temperature,stirred for 16 h, then quenched with water (20 mL), and extracted twicewith methylene chloride. The combined organic layer was washed withbrine, dried over (Na₂SO₄), and evaporated to yield 498 (0.76 g, 70%yield). Data for 498: ¹HNMR (300 MHz, CDCl₃): δ 7.40 (m, 1H), 7.30 (m,1H), 6.80 (m, 1H), 4.80 (m, 1H), 3.60 (s, 3H), 3.20 (m, 2H).

Alcohol 498 (0.7 g, 3.10 mmol) was dissolved in 10 mL methylenechloride, and the mixture cooled to 0° C. Triethylamine (0.86 mL, 6.2mmol) was added, followed by methanesulfonyl chloride (0.34 mL, 4.35mmol). The mixture was allowed to warm to room temperature and stirredfor 1 h. Methylene chloride (10 mL) was added, and the mixture washedtwice with 1N HCl, then twice with 10% aqueous sodium carbonate, andthen brine. The organic phase was dried (Na₂SO₄), and evaporated toyield the expected mesylate (0.77 g, 86% yield). Data: ¹HNMR (300 MHz,CDCl₃): δ 7.40 (m, 1H), 7.20 (d, J=3 Hz, 1H), 6.85 (m, 1H), 4.90 (m,1H), 3.00 (s, 3H).

A solution of the above mesylate (0.77 g, 2.30 mmol) indimethylformamide (5 mL) was treated with sodium azide (0.66 g, 10.15mmol) and the mixture heated to 80° C. for 3 h. The reaction mixture wascooled to room temperature, diluted with ethyl acetate (50 mL), andwashed with brine (2×50 mL). Drying (Na₂SO₄), and evaporation providedazide 499 (0.52, 83% yield) as a yellow oil of suitable purity for usein subsequent reactions.

Synthesis of Triazole 410

A solution of alkyne 173 (100 mg, 0.127 mmol) in tetrahydrofuran (10 mL)was treated with azide 499 (0.05 g, 0.19 mmol),N,N-diisopropylethylamine (0.03 mL, 0.15 mmol) and copper (I) iodide(0.02 g, 0.127 mmol), and the mixture was stirred under argon at roomtemperature for 16 h. The reaction mixture was diluted with ethylacetate (50 mL), and washed with brine (2×50 mL). The organic phase wasdried and evaporated. The residue was purified by preparative thin layerchromatography (using 90% CH₂Cl₂, 0% MeOH, 0.1% NH₄OH as eluant) toprovide 410 (71 mg, 77% yield) as a yellow solid. Data for 410: ¹HNMR(300 MHz, CDCl₃, partial): δ 7.50 (s, 1H), 7.32 (m, 1H), 7.10 (s, 1H),6.80 (t, J=3 Hz, 1H), 5.0 (m, 1H), 4.60–4.35 (m, 2H), 4.01 (m, 1H), 3.6(m, 1H).

Synthesis of Triazole 411

This compound was made from alkyne 173 and the required3-(4-chlorophenoxy)phenyl isoxazoline azide (synthesized from3-(4-chlorophenoxy)benzaldehyde using the same procedure described abovefor the synthesis of azide 499) using the same procedure described abovefor the synthesis of triazole 410. Data for 411: ¹H-NMR (300 MHz, CDCl₃,partial): δ 7.50 (s, 1H), 7.10–7.30 (m, 4H), 6.90 (s, 1H), 6.80 (s, 1H),5.02 (m, 1H), 4.50–4.70 (m, 2H), 4.35 (d, J=3 Hz, 1H), 4.0 (m, 1H), 3.60(t, J=7 Hz, 2H).

Example 58 Synthesis of Triazoles 412–414

These triazoles were synthesized using the chemistry illustrated fortriazole 412 shown in Scheme 78. Hydroxyiminoyl chloride 501 wasconverted to chiral, non-racemic alcohol 502 which was transformed toazide 503. The cycloaddition of alkyne 173 with azide 503 yieldedtriazole 412.

Synthesis of Azide 503

A solution of 3,5-difluorobenzaldehyde (2.0 g, 14.0 mmol) andhydroxylamine hydrochloride (1.07 g, 15.4 mmol) in ethanol (40 mL) andwater (80 mL) was cooled to 4° C., and 2.3 mL NaOH (50% w/w) was added.The reaction mixture was stirred for 3 h at room temperature. Thereaction mixture was adjusted to pH 6.0, and partitioned with methylenechloride and water. The aqueous layer was extracted twice with methylenechloride, and the combined organic layer was washed with brine, dried(Na₂SO₄), and evaporated to yield 500 (2.01 g, 91% yield) as a whitesolid. Data for 500: ¹HNMR (300 MHz, CDCl₃): δ 7.82 (s, 1H), 6.80 (m,1H), 6.60 (m, 1H).

To a solution of oxime 500 (2.01 g, 12.7 mmol) in dimethylformamide (10mL) was added N-chlorosuccinimide (1.7 g, 12.7 mmol). The reactionmixture was warmed to 50° C. for 1 h. The reaction was diluted withethyl acetate (50 mL), and washed with brine. The organic phase wasdried (Na₂SO₄), and evaporated to yield 501 (2.45 g, 100% yield). Datafor 501: ¹HNMR (300 MHz, CDCl₃): δ 8.0 (s, 1H), 7.40 (d, J=2 Hz, 1H),6.80 (m, 1H).

To a solution of allyl alcohol (0.7 mL, 10.30 mmol) in 20 mL CHCl₃ wasadded a 1 M diethylzine solution in hexane (12.4 mL, 12.40 mmol) at −5to 0° C. After stirring for 10 min, (+)-diisopropyl tartrate (0.5 mL,2.10 mmol) was added and the solution was stirred for 1 h at 0° C. Themilky solution was cooled to −20° C. and 20 mL CHCl₃ and dioxane (5 mL)was added. Then hydroximinoyl chloride 501 (1.80 g, 9.40 mmol) was addedin portions at −20 to −15° C. The solution was stirred for 3 h at −150°C., then poured into 100 mL saturated aqueous NH₄Cl and extracted withCHCl₃ (3×100 mL). The combined organic extract was washed with brine,dried Na₂SO₄, and evaporated. The residue was purified byflash-chromatography (eluting with 30% ethyl acetate/hexane), to affordcrude material which was recrystallized from ethyl acetate and hexane toyield 502 (0.75 g, 75% yield). Data for 502: ¹HNMR (300 MHz, CDCl₃): δ7.20 (m, 2H), 6.80 (m, 1H), 4.96 (m, 1H), 3.90 (m, 1H), 3.70 (m, 1H),3.30 (m, 2H), 2.10 (m, 1H).

Alcohol 502 (0.74 g, 3.47 mmol) was dissolved in 10 mL methylenechloride, and the mixture cooled to 0° C. Triethylamine (1.0 mL, 6.94mmol) was added, followed by methanesulfonyl chloride (0.4 mL, 4.85mmol). The mixture was allowed to warm to room temperature and stirredfor 1 h. Methylene chloride (10 mL) was added, and the mixture washedtwice with 1 N HCl, then twice with 10% aqueous sodium carbonate, andthen brine. The organic phase was dried (Na₂SO₄), and evaporated toyield the mesylate (0.93 g, 92% yield). Data: ¹HNMR (300 MHz, CDCl₃): δ7.15 (m, 2H), 6.85 (m, 1H), 5.01 (m, 1H), 4.33 (m, 2H), 3.00 (s, 3H)

A solution of the above mesylate (0.93 g, 3.19 mmol) indimethylformamide (10 mL) was treated with sodium azide (0.83 g, 12.7mmol) and the mixture heated to 80° C. for 3 h. The reaction mixture wascooled to room temperature, diluted with ethyl acetate (50 mL), andwashed with brine (2×50 mL). Drying (Na₂SO₄), and evaporation providedazide 503 (0.65, 86% yield) as a yellow oil of suitable purity for usein subsequent reactions. Data for 503: ¹HNMR (300 MHz, CDCl₃): δ 7.20(m, 2H), 6.80 (m, 1H), 4.95 (m, 1H), 3.54 (dd, J=4, 15 Hz, 1H), 3.00(dd, J=7, 10 Hz, 1H).

Synthesis of Triazole 412

A solution of alkyne 173 (100 mg, 0.127 mmol) in tetrahydrofuran (10 mL)was treated with azide 503 (0.045 g, 0.19 mmol),N,N-diisopropylethylamine (0.03 mL, 0.15 mmol) and copper (I) iodide(0.02 g, 0.127 mmol), and the mixture was stirred under argon at roomtemperature for 16 h. The reaction mixture was diluted with ethylacetate (50 mL), and washed with brine (2×50 mL). The organic phase wasdried and evaporated. The residue was purified by preparative thin layerchromatography (using 80% CH₂Cl₂, 20% MeOH, 0.1% NH₄OH as eluant) toprovide 412 (96 mg, 74% yield) as a yellow solid. Data for 412: ¹HNMR(300 MHz, CDCl₃, partial): δ 8.50 (s, 1H), 7.10 (m, 1H), 7.00 (m, 1H),6.80 (m, 1H), 5.10 (m, 1H), 4.70–4.50 (m, 2H), 4.01 (m, 1H), 3.80 (m,1H).

Synthesis of Triazole 413

This compound was made from alkyne 173 and the required3,5-dichlorophenyl isoxazoline azide (produced from3,5-dichlorobenzaldehyde as described above for the synthesis of azide503) using the same procedure described above for the synthesis of 412.Data for 413: ¹H-NMR (300 MHz, CDCl₃, partial): δ 9.20 (s, 1H), 7.50 (m,1H), 7.35 (m, 1H), 5.10 (m, 2H), 4.90 (m, 1H), 4.60 (d, J=5 Hz, 1H),4.50 (m, 2H), 4.40 (d, J=3 Hz, 1H), 4.00 (m, 1H), 3.60 (m, 2H), 3.20 (s,3H).

Synthesis of Triazole 414

This compound was made from alkyne 173 and the required piperonylisoxazoline azide (produced from piperonaldehyde as described above forthe synthesis of azide 503) using the same procedure described above forthe synthesis of 412. Data for 414: ¹H-NMR (300 MHz, CDCl₃, partial): δ8.80 (s, 1H), 7.30 (m, 1H), 7.20 (s, 1H), 7.00 (m, 1H), 6.80 (m, 1H),6.0 (s, 1H), 4.95 (m, 2H), 4.80–4.20 (m, 8H), 4.00 (m, 1H), 3.70 (t, J=3Hz, 3H).

Example 59 Synthesis of Thiazole 415

Scheme 79 depicts the synthesis of thiazole 415. Mesylate 504 wasconverted to nitrile 505 which was then hydrolyzed to afford amide 506.Amide 506 was treated with Lawesson's reagent to give the thioamide 507,which was subsequently converted to thiazole 509 by heating in thepresence of acyl bromide 508. Alkyation of amine 171 then providedthiazole 415.

Synthesis of Bromide 509

Under an argon atmosphere, a mixture of mesylate 504 (1.67 g, 5 mmol;for a synthesis see Example 39) and NaCN (1.25 g, 25 mmol) in 15 mL ofDMF was heated at 120° C. for 2 h. The reaction mixture was diluted withEtOAc, washed with brine, dried (MgSO₄), concentrated and crystallizedin EtOAc/hexane to afford nitrile 505 (1.20 g, 90% yield). Data for 505:¹HNMR (300 MHz, CDCl₃): δ 7.56 (d, J=9 Hz, 2H), 7.53 (d, J=9 Hz, 2H),5.05 (m, 1H), 3.60 (dd, J=11, 17 Hz, 1H), 3.25 (dd, J=6, 17 Hz, 1H),2.51 (dd, J=5, 17 Hz, 1H), 2.73 (dd, J=7, 17 Hz, 1H).

A mixture of nitrile 505 (1.0 g, 3.77 mmol) and KOH (0.5 g, 8.93 mmol)in 16 mL of tert-butanol and 2 mL of water was heated to reflux for 2 h.The reaction mixture was cooled to room temperature and diluted withwater. The desired amide 506 was collected by filtration (0.85 g, 80%yield). Data for 506: ¹HNMR (300 MHz, DMSO): δ 7.66 (d, J=8 Hz, 2H),7.61 (d, J=8 Hz, 2H), 7.43 (s, 1H), 6.97 (s, 1H), 4.99 (m, 1H), 3.52(dd, J=11, 17 Hz, 1H), 3.15 (dd, J=7, 17 Hz, 1H), 2.51 (dd, J=7, 14 Hz,1H), 2.39 (dd, J=7, 14 Hz, 1H).

A mixture of 506 (220 mg, 0.78 mmol) and Lawesson's reagent (187 mg,0.46 mmol) in THF (3 mL) was refluxed under argon for 2 h. The reactionwas diluted with EtOAc, washed with brine, dried over MgSO₄ andconcentrated under vacuum. Recrystallization of the crude product fromEtOAc afforded 507 (180 mg, 77% yield). Data for 507: MS (ESI) m/z 298.8(M+H)⁺; ¹HNMR (300 MHz, CDCl₃): δ 7.56 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz,2H), 7.46 (br s, 2H), 5.15 (m, 1H), 3.52 (dd, J=10, 17 Hz, 1H), 3.27(dd, J=8, 17 Hz, 1H), 3.12 (d, J=12 Hz, 2H).

To a solution of 508 (190 mg, 0.83 mmol; prepared as in Eur. J. Org.Chem. 2001, pp. 3789–3795) in THF (8 mL) and MeOH (2 mL) was added 507(150 mg, 0.50 mmol). After refluxing for 2 h, the reaction wasconcentrated and crystallized in CH₂Cl₂ to provide 509 (163 mg, 77%yield). Data for 509: MS (ESI) m/z 430.7 (M+H)⁺; ¹HNMR (300 MHz, CDCl₃):δ 7.56 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.41 (s, 1H), 5.26 (m,1H), 4.02 (dd, J=4, 15 Hz, 1H), 3.85–3.75 (m, 3H), 3.69–3.47 (m, 4H).

Synthesis of Thiazole 415

A mixture of 509 (56 mg, 0.13 mmol), amine 171 (96 mg, 0.13 mmol),Hunig's base (170 mg, 1.3 mmol) and KI (22 mg, 0.13 mmol) in THF (4 mL)was refluxed for 24 h. The THF was removed under vacuum and the residuewas dissolved in EtOAc. The solution was washed with brine, dried overMgSO₄, concentrated and purified by chromatography on silica gel(eluant: 25:1:0.1/CH₂Cl₂:MeOH:NH₃-H₂O) to provide thiazole 415 (52 mg,37% yield). Data for 415: MS (ESI) m/z 1083.7 (M+H)⁺, 542.2 (100%);¹HNMR (300 MHz, CDCl₃, partial): δ 7.46 (s, 4H), 6.78 (s, 1H), 5.10 (m,1H), 3.24 (s, 3H), 0.83 (t, J=7 Hz, 3H).

Incorporation by Reference

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting on the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1. A compound having the formula:

or a pharmaceutically acceptable salt, ester, or prodrug thereof;wherein A at each occurrene is carbon; B is selected from the groupconsisting of O, NR², S(O)_(r), C═O, C═S, and C═NOR³, p is 0; q, at eachoccurrence, independently is 0 or 1; r is 0, 1 or 2; R², at eachoccurrence, independently is selected from the group consisting of: a)hydrogen, b) S(O)_(r)R⁴, c) formyl, d) C₁₋₈ alkyl, e) C₂₋₈ alkenyl, f)C₂₋₈ alkynyl, g) C₁₋₈ alkoxy, h) C₁₋₈ alkylthio, i) C₁₋₈ acyl, j)saturated, unsaturated, or aromatic C₃₋₈ carbocycle, and k) saturated,unsaturated, or aromatic 5–10 membered heterocycle containing one ormore heteroatoms selected from the group consisting of nitrogen, oxygen,and sulfur, wherein any of d)–k) optionally is substituted with one ormore moieties selected from the group consisting of carbonyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN,NO₂, —NR³R³, —OR³, —S(O)_(r)R⁴, —S(O)_(r)NR³R³, —C(O)R³, —C(O)OR³,—OC(O)R³, —C(O)NR³R³, and —OC(O)NR³R³; alternatively, two R² groups,taken together with the atom to which they are bonded, form i) 5–8membered saturated or unsaturated carbocycle, or ii) 5–8 memberedsaturated or unsaturated heterocycle containing one or more atomsselected from the group consisting of nitrogen, oxygen, and sulfur,wherein i)–ii) optionally is substituted with one or more moietiesselected from the group consisting of carbonyl, F, Cl, Br, I, CN, NO₂,—NR³R³, —OR³, —S(O)_(r)R⁴, —S(O)_(r)NR³R³, —C(O)R³, —C(O)OR³, —OC(O)R³,—C(O)NR³R³, —OC(O)NR³R³, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl; R³, at each occurrence, independently isselected from the group consisting of: a) hydrogen, b) C₁₋₈ alkyl, c)C₂₋₈ alkenyl, d) C₂₋₈ alkynyl, e) C₁₋₈ acyl, f) saturated, unsaturated,or aromatic C₃₋₈ carbocycle, and g) saturated, unsaturated, or aromatic5–10 membered heterocycle containing one or more heteroatoms selectedfrom the group consisting of nitrogen, oxygen, and sulfur, wherein anyof b)–h) optionally is substituted with one or more moieties selectedfrom the group consisting of carbonyl, F, Cl, Br, I, CN, NO₂, —NR⁶R⁶,—OR⁶, —S(O)_(r)R⁶, —S(O)_(r)NR⁶R⁶, —C(O)R⁶, —C(O)OR⁶, —OC(O)R⁶,—C(O)NR⁶R⁶, —OC(O)NR⁶R⁶, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl; alternatively, two R³ groups, taken togetherwith the atom to which they are bonded, form i) a 5–7 membered saturatedor unsaturated carbocycle, or ii) a 5–7 membered saturated orunsaturated heterocycle containing one or more atoms selected from thegroup consisting of nitrogen, oxygen, and sulfur, wherein i)–ii)optionally is substituted with one or more moieties selected from thegroup consisting of carbonyl, F, Cl, Br, I, CN, NO₂, —NR⁶R⁶, —OR⁶,—S(O)_(r)R⁶, —S(O)_(r)NR⁶R⁶, —C(O)R⁶, —C(O)OR⁶, OC(O)R⁶, —C(O)NR⁶R⁶,—OC(O)NR⁶R⁶, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl; R⁴ is selected from the group consisting of: a)hydrogen, b) —NR³R³, c) —NR³OR³, d) —NR³NR³R³ e) —NHC(O)R³, f)—C(O)NR³R³, g) —N₃, h) C₁₋₈ alkyl, i) C₂₋₈ alkenyl, j) C₂₋₈ alkynyl, k)saturated, unsaturated, or aromatic C₃₋₈ carbocycle, and l) saturated,unsaturated, or aromatic 5–10 membered heterocycle containing one ormore heteroatoms selected from the group consisting of nitrogen, oxygen,and sulfur, wherein any of h)–l) optionally is substituted with one ormore moieties selected from the group consisting of carbonyl, F, Cl, Br,I, CN, NO₂, —NR³R³, —OR³, —SR³, —S(O)_(r)R⁵, —S(O)_(r)NR³R³, —C(O)R³,—C(O)OR³, —OC(O)R³, —C(O)NR³R³, —OC(O)NR³R³, C₁₋₆ alkyl, C₁₋₆ alkenyl,C₁₋₆ alkynyl, C₁₋₆ acyl, aryl, substituted aryl, heteroaryl, andsubstituted heteroaryl; R⁵ is selected from the group consisting of: a)hydrogen, b) —NR³R³, c) —NR³OR³, d) —NR³NR³R³ e) —NHC(O)R³, f)—C(O)NR³R³, g) —N₃, h) C₁₋₈ alkyl, i) C₂₋₈ alkenyl,j) C₂₋₈ alkynyl, k)saturated, unsaturated, or aromatic C₃₋₈ carbocycle, and l) saturated,unsaturated, or aromatic 5–10 membered heterocycle containing one ormore heteroatoms selected from the group consisting of nitrogen, oxygen,and sulfur, wherein any of h)–l) optionally is substituted with one ormore moieties selected from the group consisting of F, Cl, Br, I, CN,NO₂, —NR³R³, —OR³, —SR³—C(O)R³, —C(O)OR³, —OC(O)R³, —C(O)NR³R³,—OC(O)NR³R³, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, C₁₋₆ acyl, aryl,substituted aryl, heteroaryl, and substituted heteroaryl; R⁶, at eachoccurrence, independently is selected from the group consisting of:hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, C₁₋₆ acyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl; alternatively, twoR⁶ groups taken together are —(CH₂)_(s)—, wherein s is 1, 2, 3, 4, or 5;D-E is

E is selected from the group consisting of:

d) 5–10 membered aromatic heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, andoptionally substituted with one or more R¹³ groups; and e) C₅₋₁₀aromatic carbocycle, optionally substituted with one or more R¹³ groups;R⁷ selected from the group consisting of: a) hydrogen, b) carbonyl, c)formyl, d) F, e) Cl, f) Br, g) I, h) CN, i) NO₂, j) OR³, k) —S(O)_(r)R⁵,l) —S(O)_(i)N═R², m) —C(O)R², n) —C(O)OR³, o) —OC(O)R², p) —C(O)NR²R²,q) —OC(O)NR²R², r) —C(═NR¹²)R², s) —C(R²)(R²)OR³, t) —C(R²)(R²)OC(O)R²,u) —C(R²)(OR³)(CH₂)_(r)NR²R², v) —NR²R², w) —NR²OR³, x) —N(R²)C(O)R², y)—N(R²)C(O)OR³, z) —N(R²)C(O)NR²R², aa) —N(R²)S(O)_(r)R⁵, bb)—C(OR⁶)(OR⁶)R², cc) —C(R²)(R³)NR²R², dd) —C(R²)(R³)NR²R¹², ee) ═NR¹²,ff) —C(S)NR²R², gg) —N(R²)C(S)R², hh) —OC(S)NR²R², ii) —N(R²)C(S)OR³,jj) —N(R²)C(S)NR²R², kk) —SC(O)R^(2, ll) C) ₁₋₈ alkyl, mm) C₂₋₈ alkenyl,nn) C₂₋₈ alkynyl, oo) C₁₋₈ alkoxy, pp) C₁₋₈ alkylthio, qq) C₁₋₈ acyl,rr) saturated, unsaturated, or aromatic C₅₋₁₀ carbocycle, and ss)saturated, unsaturated, or aromatic 5–10 membered heterocycle containingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, wherein any of ll)–ss) optionally is substitutedwith one or more moieties selected from the group consisting of:carbonyl; formyl; F; Cl; Br; I; CN; NO₂; OR³; —S(O)_(r)R⁵;—S(O)_(r)N═R², —C(O)R²; —C(O)OR³; —OC(O)R²; —C(O)NR²R²; —OC(O)NR²R²;—C(═NR¹⁰)R²; —C(R²)(R²)OR³; —C(R²)(R²)OC(O)R²;—C(R²)(OR³)(CH₂)_(r)NR²R²; —NR²R²; —NR²OR³; —NR²C(O)R²; —NR²C(O)OR³;—NR²C(O)NR²R²; —NR²S(O)_(r)R⁵; —C(OR⁶)(OR⁶)R²; —C(R²)(R³)NR²R²;—C(R²)(R³)NR²R¹²; ═NR¹²; —C(S)NR²R²; —NR²C(S)R²; —OC(S)NR²R²;—NR²C(S)OR³; —NR²C(S)NR²R²; —SC(O)R²; C₂₋₅ alkenyl; C₂₋₅ alkynyl; C₁₋₈alkoxy; C₁₋₈ alkylthio; C₁₋₈ acyl; saturated, unsaturated, or aromaticC₅₋₁₀ carbocycle, optionally substituted with one or more R⁸ groups; andsaturated, unsaturated, or aromatic 5–10 membered heterocycle containingone or more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, and optionally substituted with one or more R⁸groups; R⁸ is selected from the group consisting of: hydrogen; F; Cl;Br; I; CN; NO₂; OR⁶; aryl; substituted aryl; heteroaryl; substitutedheteroaryl; and C₁₋₆ alkyl, optionally substituted with one or moremoieties selected from the group consisting of aryl, substituted aryl,heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO₂, and OR⁶;alternatively, R⁷ and R⁸ taken together are —O(CH₂)_(r)O—; R⁹, at eachoccurrence, independently is selected from the group consisting of:hydrogen, F, Cl, Br, I, CN, OR³, NO₂, —NR²R², C₁₋₆ alkyl, C₁₋₆ acyl, andC₁₋₆ alkoxy; R¹⁰ selected from the group consisting of: a) saturated,unsaturated, or aromatic C₅₋₁₀ carbocycle, b) saturated, unsaturated, oraromatic 5–10 membered heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, c)-X-C₁₋₆ alkyl-saturated, unsaturated, or aromatic 5–10 memberedheterocycle containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, d) saturated, unsaturated,or aromatic 10-membered bicyclic ring system optionally containing oneor more heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur, e) saturated, unsaturated, or aromatic 13-memberedtricyclic ring system optionally containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, andf) R⁹, wherein any of a)–e) optionally is substituted with one or moreR¹³ groups, and X is 0 or NR³; alternatively, R¹⁰ and one R⁹ group,taken together with the atoms to which they are bonded, form a 5–7membered saturated or unsaturated carbocycle, optionally substitutedwith one or more R¹³ groups; or a 5–7 membered saturated or unsaturatedheterocycle containing one or more atoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, and optionally substitutedwith one or more R¹³ groups; R¹¹ at each occurrence, independently isselected from the group consisting of: hydrogen; an electron-withdrawinggroup; aryl; substituted aryl; heteroaryl; substituted heteroaryl; andC₁₋₆ alkyl, optionally substituted with F, Cl, or Br; alternatively, anyR¹¹ and R⁸, taken together with the atoms to which they are bonded, forma 5–7 membered saturated or unsaturated carbocycle, optionallysubstituted with one or more R¹³ groups; or a 5–7 membered saturated orunsaturated heterocycle containing one or more atoms selected from thegroup consisting of nitrogen, oxygen, and sulfur, and optionallysubstituted with one or more R¹³ groups; R¹² is selected from the groupconsisting of: —NR²R², —OR³, —OC(O)R², —OC(O)OR³, —NR²C(O)R²,—NR²C(O)NR²R², —NR²C(S)NR²R², and —NR²C(═NR²)NR²R²; R¹³, at eachoccurrence, independently is selected from the group consisting of: a)hydrogen, b) carbonyl, c) formyl d) F, e) Cl, f) Br, g) I, h) CN, i)NO₂, j) OR³, k) —S(O)_(r)R⁵, l) —S(O)_(r)N═R³, m) —C(O)R², n) —C(O)OR³,o) —OC(O)R², p) —C(O)NR²R², q) —OC(O)NR²R², r) —C(═NR¹²)R², s)—C(R²)(R²)OR³, t) —C(R²)(R²)OC(O)R², u) —C(R²)(OR³)(CH₂)_(r)NR²R², v)—NR²R², w) —NR²OR³, x) —N(R²)C(O)R², y) —N(R²)C(O)OR³, z)—N(R²)C(O)NR²R², aa) —N(R²)S(O)_(r)R⁵, bb) —C(OR⁶)(OR⁶)R², cc)—C(R²)(R³)NR²R², dd) —C(R²)(R³)NR¹²R², ee) ═NR¹², ff) —C(S)NR²R², gg)—N(R²)C(S)R², hh) —OC(S)NR²R², ii) —N(R²)C(S)OR³, jj) —N(R²)C(S)NR²R²,kk) —SC(O)R², ll) C₁₋₈ alkyl, mm) C₂₋₈ alkenyl, nn) C₂₋₈ alkynyl, oo)C₁₋₈ alkoxy, pp) C₁₋₈ alkylthio, qq) C₁₋₈ acyl, rr) saturated,unsaturated or aromatic C₅₋₁₀ carbocycle, ss) saturated, unsaturated, oraromatic 5–10 membered heterocycle containing one or more heteroatomsselected from the group consisting of nitrogen, oxygen, and sulfur, tt)saturated, uusaturated, or aromatic 10-membered bicyclic ring systemoptionally containing one or more heteroatoms selected from the groupconsisting of nitrogen, oxygen, and sulfur, and uu) saturated,unsaturated, or aromatic 13-membered tricyclic ring system optionallycontaining one or more heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur, wherein any of ll)–uu) optionally issubstituted with one or more moieties selected from the group consistingof: carbonyl; formyl; F; Cl; Br; I; CN; NO₂; OR³; —S(O)_(r)R⁵;—S(O)_(r)N═R², —C(O)R²; —C(O)OR³; —OC(O)R²; —C(O)NR²R²; —OC(O)NR²R²;—C(═NR¹²)R²; —C(R²)(R²)OR³; —C(R²)(R²)OC(O)R²;—C(R²)(OR³)(CH₂)_(r)NR²R²; —NR²R²; —NR²OR³; —NR²C(O)R²; —NR²C(O)OR³;—NR²C(O)NR²R²; —NR²S(O)_(r)R⁵; —C(OR⁶)(OR⁶)R²; —C(R²)(R³)NR²R²;—C(R²)(R³)NR²R¹²; ═NR¹²; —C(S)NR²R²; —NR²C(S)R²; —OC(S)NR²R²;—NR²C(S)OR³; —NR²C(S)NR²R²; —SC(O)R²; C₁₋₈ alkyl, C₂₋₈ alkenyl; C₂₋₈alkynyl; C₁₋₈ alkoxy; C₁₋₈ alkylthio; C₁₋₈ acyl; saturated, unsaturated,or aromatic C₃₋₁₀ carbocycle optionally substituted with one or more R⁷groups; and saturated, unsaturated, or aromatic 3–10 memberedheterocycle containing one or more heteroatoms selected from the groupconsisting of nitregen, oxygen, and sulfur, and substituted with one ormore R⁷ groups; G is selected from the group consisting of:

t, at each occurrence, independently is 0, 1, 2, or 3; R¹⁴ is selectedfrom the group consisting of: a) hydrogen, b) C₁₋₆-alkyl, c) C₂₋₆alkenyl , d) C₂₋₆ alkynyl, e) —C(O)—R³, f) —C(O)—C₁₋₆ alkyl-R³, g)—C(O)—C₂₋₆ alkenyl-R³, h) —C(O)—C₂₋₆ alkynyl-R³, i) —C₁₋₆ alkyl-J-R³, j)—C₂₋₆ alkenyl-J-R³; and k) —C₂₋₆ alkynyl-J-R³; wherein (i) any of b)–d)optionally is substituted with one or more substituents selected fromthe group consisting of: F, Cl, Br, I, aryl, substituted aryl,heteroaryl, substituted heteroaryl, —OR³, —O—C₁₋₆ alkyl-R², —O—C₂₋₆alkenyl-R², —O—C₂₋₆ alkynyl-R², and —NR²R²; and (ii) J is selected fromthe group consisting of: —OC(O)—, —OC(O)O—, —OC(O)NR²—, —C(O)NR²—,—NR²C(O)—, —NR²C(O)O—, —NR²C(O)NR²— —NR²C(NH)NR²—, and S(O)_(r); and R¹⁵is selected from the group consisting of: hydrogen; C₁₋₁₀ alkyl,optionally substituted with one or more R¹³ groups; C₁₋₆ acyl,optionally substituted with one or more R¹³ groups; aryl; substitutedaryl; heteroaryl; substituted heteroaryl; arylalkyl; substitutedarylalkyl; and a macrolide.
 2. The compound according to claim 1, havingthe formula:

wherein A, E, and G are as defined in claim
 1. 3. The compound accordingto claim 1, wherein E has the formula:

wherein R⁹ and R¹⁰, at each occurrence, are as defined in claim
 1. 4.The compound according to claim 1, wherein E has the formula:

wherein R¹⁰ is as defined in claim
 1. 5. The compound according to claim3, wherein R¹⁰ has the formula:

wherein K is selected from the group consisting of O, NR², and S(O)_(r),and x is 0, 1 , 2, or
 3. 6. The compound according to claim 5, wherein Kis oxygen.
 7. The compound according to claim 5, wherein x is
 1. 8. Thecompound according to claim 1, wherein G has the formula:

and R¹⁵ is a macrolide.
 9. The compound according to claim 1, wherein Ghas the formula:

and R¹⁵ is a macrolide.
 10. The compound according to claim 1, whereinR¹⁵ is selected from the group consisting of:

and pharmaceutically acceptable salts, esters and prodrugs thereof,wherein R¹⁷ is selected from the group consisting of: hydrogen, hydroxyprotecting group, R³, and -V-W-R¹³, wherein V is —C(O), —C(O)O—,—C(O)NR², or absent, and W is C₁₋₆ alkyl, or absent; alternatively R¹⁷and R¹⁴, taken together with the atoms to which they are bonded, form:

Q is selected from the group consisting of: —NR²CH₂—, —CH₂—NR²—, —C(O)—,—C(═NR²)—, —C(═NOR³)—, —C(═N—NR²R²)—, —CH(OR³)—, and —CH(NR²R²)—; R¹⁸ isselected from the group consisting of: i) C₁₋₆ alkyl, ii) C₂₋₆ alkenyl,and iii) C₂₋₆ alkynyl; wherein any of i)–iii) optionally is substitutedwith one or more moieties selected from the group consisting of —OR³,aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R¹⁹ isselected from the group consisting of: a) OR¹⁷, b) C₁₋₆ alkyl, c) C₂₋₆alkenyl, d) C₂₋₆ alkynyl, e) —NR²R², f) —C(O)R³, g) —C(O)—C₁₋₆alkyl-R¹³, h) —C(O)—C₂₋₆ alkenyl-R³, and i) —C(O)—C₂₋₆ alkynyl-R¹³,wherein any of b)–d) optionally is substituted with one or more R¹³groups; alternatively, R¹⁴ and R¹⁹, taken together with the atoms towhich they are bonded, form:

wherein L is CH or N, and R²³ is —OR³, or R³; R²⁰ is —OR¹⁷;alternatively, R¹⁹ and R²⁰, taken together with the atoms to which theyare bonded, form a 5-membered ring by attachment to each other through alinker selected from the group consisting of: —OC(R²)(R²)O—, —OC(O)O—,—OC(O)NR²—, —NR²C(O)O—, —OC(O))NOR³—, —N(OR³)C(O)O—, —OC(O)N—NR²R²—,—N(NR²R²)C(O)O—, —OC(O)CHR²—, —CHR²C(O)O—, —OC(S)O—, —OC(S)NR²—,—NR²C(S)O—, —OC(S)NOR³—, —N(OR³)C(S)O—, —OC(S)N—NR²R²—, —N(NR²R²)C(S)O—,—OC(S)CHR²—, and —CHR²C(S)O—; alternatively, Q, R¹⁹, and R²⁰, takentogether with the atoms to which they are bonded, form:

wherein M is O or NR²; R²¹ is selected from the group consisting of:hydrogen, F, Cl, Br, and C₁₋₆ alkyl; R²², at each occurrence,independently is selected from the group consisting of: hydrogen, —OR³,—O-hydroxy protecting group, —O—C₁₋₆ alkyl-J-R¹³, —O—C₂₋₆ alkenyl-J-R¹³,—O—C₁₋₆ alkynyl-J-R¹³, and —NR²R²; alternatively, two R²² groups takentogether are ═O, ═N—OR³, or ═N—NR²R²; and R², R³, R¹³, R¹⁴, and J are asdescribed in claim
 1. 11. The compound according to claim 1, wherein Ghas the formula selected from the group consisting of:

and R¹⁵ has the formula selected from the group consisting of:


12. The compound according to claim 1, wherein G has the formula:

wherein n=1, 2, 3, or
 4. 13. The compound according to claim 1, whereinG has the formula:

wherein n=1, 2, 3, or
 4. 14. The compound according to claim 1, whereinG has the formula selected from the group consisting of:


15. A compound having the structure corresponding to any of thestructures listed below: Compound Number Structure 145

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or a pharmaceutically acceptable salt, ester, or prodrug thereof.
 16. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier.
 17. A method of treating amicrobial infection in a mammal comprising administering to the mammalan effective amount of a compound according to claim
 1. 18. The methodaccording to claim 17 wherein the compound is administered orally,parentally, or topically.
 19. A pharmaceutical composition comprising acompound according to claim 15 and a pharmaceutically acceptablecarrier.
 20. The compound according to claim 1, wherein G has theformula:

and R¹⁵ is a macrolide.
 21. A pharmaceutical composition comprising acompound according to claim 8 and a pharmaceutically acceptable carrier.22. A pharmaceutical composition comprising a compound according toclaim 9 and a pharmaceutically acceptable carrier.
 23. A pharmaceuticalcomposition comprising a compound according to claim 20 and apharmaceutically acceptable carrier.